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Effect of coenzyme Q10 intake on endogenous coenzyme Q content, mitochondrial electron transport chain, antioxidative defenses, and life span of mice
Abstract
The main purpose of this study was to determine whether intake of coenzyme Q10, which can potentially act as both an antioxidant and a prooxidant, has an impact on indicators of oxidative stress and the aging process. Mice were fed diets providing daily supplements of 0, 93, or 371 mg CoQ10 /kg body weight, starting at 3.5 months of age. Effects on mitochondrial superoxide generation, activities of oxidoreductases, protein oxidative damage, glutathione redox state, and life span of male mice were determined. Amounts of CoQ9 and CoQ10, measured after 3.5 or 17.5 months of intake, in homogenates and mitochondria of liver, heart, kidney, skeletal muscle, and brain increased with the dosage and duration of CoQ10 intake in all the tissues except brain. Activities of mitochondrial electron transport chain oxidoreductases, rates of mitochondrial O2-* generation, state 3 respiration, carbonyl content, glutathione redox state of tissues, and activities of superoxide dismutase, catalase, and glutathione peroxidase, determined at 19 or 25 months of age, were unaffected by CoQ10 administration. Life span studies, conducted on 50 mice in each group, showed that CoQ10 administration had no effect on mortality. Altogether, the results indicated that contrary to the historical view, supplemental intake of CoQ10 elevates the endogenous content of both CoQ9 and CoQ10, but has no discernable effect on the main antioxidant defenses or prooxidant generation in most tissues, and has no impact on the life span of mice.
... Future studies will be necessary to elucidate these observations and to determine the underlying mechanisms responsible for this difference. The observed rise in CoQ 9 levels in the thorax may be linked to the higher demand for CoQ, driven by the abundance of mitochondria typically found in muscle tissue, a phenomenon previously demonstrated in both mice and rats [29]. On the other hand, the abdomen, characterized by the presence of the reproductive system and adipose tissue, could retain ubiquinone. ...
... Given its lipophilic nature, the distribution of Co Q could also be influenced by the lipid content of the tissue [14]. Due to the absence of the blood-brain barrier in Drosophila head, resulting in a lower selectivity to the passage of molecules, the increase in CoQ was of the same magnitude to that observed in other segments, which contrasts with findings in mice [29] and rats [27], where the brain has the lowest capacity for CoQ uptake. However, in our study, the fly head segment did not exclusively consist of brain tissue. ...
... Considering these data and the variations in the distribution of endogenous CoQ among the body segments of fruit flies over time and by sex, it is also conceivable that the absorption and subsequent efficacy of exogenous CoQ could vary significantly and be highly tissue specific. This has already been demonstrated in studies involving mice [29] and rats [26,27]. ...
... The addition of CoQ 10 to rodent chow is a common feeding method. Similar to studies in human patients, high doses have been used to study CoQ 10 uptake in mice and rats [162,163]. As the CoQ 10 -supplemented chow is digested, the hydrophobic CoQ 10 is taken up at the GI tract. ...
... This may generate conflicting outcomes when comparing rats or mice with guinea pigs, which solely produce CoQ10 as the endogenous isoform. Several studies in both rats and mice have shown that supplementation of CoQ10 increases endogenous CoQ9 levels in various tissues, serum, and mitochondria [163,173,174]. This is likely due to a sparing effect of supplemented CoQ10 on the endogenous CoQ9 pool in which the addition of CoQ10 to the cellular CoQ pool "spares" the turnover of CoQ9; a similar phenomenon is observed when CoQ10 supplements preserve levels of α-tocopherol or the tissue content of CoQ9 [175,176]. ...
... This may generate conflicting outcomes when comparing rats or mice with guinea pigs, which solely produce CoQ 10 as the endogenous isoform. Several studies in both rats and mice have shown that supplementation of CoQ 10 increases endogenous CoQ 9 levels in various tissues, serum, and mitochondria [163,173,174]. This is likely due to a sparing effect of supplemented CoQ 10 on the endogenous CoQ 9 pool in which the addition of CoQ 10 to the cellular CoQ pool "spares" the turnover of CoQ 9 ; a similar phenomenon is observed when CoQ 10 supplements preserve levels of α-tocopherol or the tissue content of CoQ 9 [175,176]. ...
Coenzyme Q (CoQ) is an essential lipid with many cellular functions, such as electron transport for cellular respiration, antioxidant protection, redox homeostasis, and ferroptosis suppression. Deficiencies in CoQ due to aging, genetic disease, or medication can be ameliorated by high-dose supplementation. As such, an understanding of the uptake and transport of CoQ may inform methods of clinical use and identify how to better treat deficiency. Here, we review what is known about the cellular uptake and intracellular distribution of CoQ from yeast, mammalian cell culture, and rodent models, as well as its absorption at the organism level. We discuss the use of these model organisms to probe the mechanisms of uptake and distribution. The literature indicates that CoQ uptake and distribution are multifaceted processes likely to have redundancies in its transport, utilizing the endomembrane system and newly identified proteins that function as lipid transporters. Impairment of the trafficking of either endogenous or exogenous CoQ exerts profound effects on metabolism and stress response. This review also highlights significant gaps in our knowledge of how CoQ is distributed within the cell and suggests future directions of research to better understand this process.
... The possibility of increasing CoQ10 levels in different organs or tissues through dietary supplementation has been widely explored in recent decades. Studies in rodents [153][154][155][156][157] suggest that CoQ10 administration is able to increase the amounts of CoQ10 in plasma and liver significantly, and in heart, kidney and skeletal muscle moderately. Similarly, different authors have reported increased systemic levels of CoQ10 in humans after supplementing with CoQ10 at different daily doses (100 to 2400 mg) and duration (20 days, 3 or even 16 months) in multiple trials [158][159][160][161][162]. Regarding the safety of CoQ10 supplements, different assessments in human and animals (reviewed by Hidaka et al. [163]) concluded that the endogenous biosynthesis of CoQ10 is not influenced by exogenous inputs. ...
... In C. elegans, exogenous CoQ10 prolonged life span [168]. Also, the addition of CoQ10 to the diet has been shown to increase life span in rodents, at least under certain circumstances-notwithstanding that in most of the studies in both rats and mice, CoQ10 supplementation was ineffective for increasing life span [157,169,170]. Importantly, according to the variety of used CoQ10 doses (ranged from 10 to 370 mg/Kg per day) and the duration of the different studies, the lack of effects on longevity seems, in many of these studies, not to depend on these conditions. ...
... In contrast, oxidized CoQ10 had no effect on senescence in the same model [211]. On the other hand, Sohal et al. [157] did not find effects on the activity of different antioxidant enzymes in the liver, heart, kidney, skeletal muscle, and brain of mice. In male Wistar rats, long-term supplementation with low doses of CoQ10 has been shown to attenuate age-related alveolar bone loss [173,212], prevent age-related decline in BMD [174] and reduce histological alterations in endocrine pancreas, which mainly affected β-cell mass and insulin levels in aged animals [175]. ...
Coenzyme Q (CoQ) is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. Although defects in CoQ biosynthesis in human and mouse models cause CoQ deficiency syndrome, some animals models with particular defects in the CoQ biosynthetic pathway have shown an increase in life span, a fact that has been attributed to the concept of mitohormesis. Paradoxically, CoQ levels decline in some tissues in human and rodents during aging and coenzyme Q10 (CoQ10) supplementation has shown benefits as an anti-aging agent, especially under certain conditions associated with increased oxidative stress. Also, CoQ10 has shown therapeutic benefits in aging-related disorders, particularly in cardiovascular and metabolic diseases. Thus, we discuss the paradox of health benefits due to a defect in the CoQ biosynthetic pathway or exogenous supplementation of CoQ10.
... In animal studies, CoQ 10 intake appeared to increase in antioxidative potential of tissues [10]. However, several studies insisted that the endogenous production level was enough to provide sufficient CoQ 10 to prevent deficiency in young healthy animals [11,12]. ...
... At present, the effectiveness of oral supplementation of CoQ 10 varies greatly depending upon the physiological and metabolic status of animals, health of individuals, level and period of CoQ 10 supplement, etc. [1,11,13]. Recently, it has been reported that antioxidant therapy with CoQ 10 may have beneficial effects associated with atorvastatin-induced myopathy in hyperlipidemic rats [14]. Atorvastatin, a member of the drug class known as statins used for lowering cholesterol, also inhibit the synthesis of CoQ 10 in the body, because CoQ 10 and cholesterol are both synthesized from the same precursor known as mevalonate. ...
... A study suggested that CoQ 10 supplement might directly contribute to the antioxidant defense system via potentiating the electron transport chain in the mitochondria of the liver [36], rather than modulating the expression of antioxidant enzymes in animals. They insisted that dietary CoQ 10 did not directly affect the expression of antioxidant enzymes in tissues [11,37]. According to the literatures to date, it seems that the antioxidant effects of CoQ 10 vary depending on the physiological status of animals, dosage and duration of CoQ 10 level, environmental conditions, etc. [6,9,11,38], although CoQ 10 is known to maintain the hepatic antioxidant function via the modulation of antioxidant enzymes or its antioxidant capacity under oxidative stress. ...
A total of 24 SD rats were allotted to four treatment groups such as the control (CON), 1% of cholesterol diet (CHO), 0.5% of coenzyme Q10 (COQ) and 1% of cholesterol plus 0.5% of coenzyme Q10 (CHCQ) groups to determine the effects of coenzyme Q10 (CoQ10) on the antioxidant defense system in rats. The body weight, weight gain, liver weight and abdominal fat pads were unaffected by 0.5% of CoQ10 supplement in the rats. The level of triglyceride and HDL-cholesterol levels in the blood was significantly increased (p < 0.05) by the 1% of cholesterol supplement (CHO), whereas 0.5% of CoQ10 supplement (COQ) did not alter these blood lipid indices. In the mRNA expression, there was a significant effect (P < 0.05) of the CoQ10 supplement on the mRNA expression of superoxide dismutase (SOD), although the mRNA expression of glutathione peroxidase (GPX) and glutathione S-transferase (GST) was unaffected by cholesterol or the CoQ10 supplement. Similar to mRNA expression of SOD, its activity was also significantly increased (P < 0.05) by CoQ10, but not by the cholesterol supplement effect. The activities hepatic GPX and GST were unaffected by CoQ10 and cholesterol supplements in rats. Lipid peroxidation in the CHO group resulted in a significant (p < 0.05) increase compared with that in the other groups, indicating that the CoQ10 supplement to 1% of cholesterol-fed rats alleviated the production of lipid peroxidation in the liver. In conclusion, 0.5% of the CoQ10 supplement resulted in positive effects on the hepatic antioxidant defense system without affecting blood lipid indices in 1% of cholesterol fed rats.
... Recent publications associate ubiquinol with protection of plasma low density lipoproteins (LDL) from oxidation, an important anti-atherogenic effect [25]. The pro-oxidant role of CoQ 10 is a signaling function involved in gene expression but the mechanism of this function is not fully understood [26,27]. Other functions include modulation of the permeability transition pore, thus playing a role in apoptosis [28]. ...
... Recent publications associate ubiquinol with protection of plasma low density lipoproteins (LDL) from oxidation, an important anti-atherogenic effect [25]. The pro-oxidant role of CoQ10 is a signaling function involved in gene expression but the mechanism of this function is not fully understood [26,27]. Other functions include modulation of the permeability transition pore, thus playing a role in apoptosis [28]. ...
... In mammals there is a tendency to ubiquinone to be reduced with age, but this finding depends on the tissue investigated and also the species [97]. Early studies suggested that tissue levels of ubiquinol were endogenously produced with little change with dietary supplementation except in liver and spleen; however, subsequent studies in rodents confirm that oral supplementation with CoQ 10 does increase tissue levels of both CoQ 10 and CoQ 9 in skeletal muscle, heart, and kidney [26], and when high doses (200 mg/kg) are used for 2 months in rats, brain levels are increased and are neuroprotective [112]. ...
The aging process includes impairment in mitochondrial function, a reduction in anti-oxidant activity, and an increase in oxidative stress, marked by an increase in reactive oxygen species (ROS) production. Oxidative damage to macromolecules including DNA and electron transport proteins likely increases ROS production resulting in further damage. This oxidative theory of cell aging is supported by the fact that diseases associated with the aging process are marked by increased oxidative stress. Coenzyme Q10 (CoQ10) levels fall with aging in the human but this is not seen in all species or all tissues. It is unknown whether lower CoQ10 levels have a part to play in aging and disease or whether it is an inconsequential cellular response to aging. Despite the current lay public interest in supplementing with CoQ10, there is currently not enough evidence to recommend CoQ10 supplementation as an anti-aging anti-oxidant therapy.
... Therefore, CoQ 10 supplements could prove to be particularly interesting for aging. Several studies conducted in preclinical models have reported positive effects of dietary CoQ 10 regarding aging, particularly under certain conditions associated with oxidative stress (26)(27)(28)(29)(30)(31)(32)(33)(34). ...
... Some beneficial effects of CoQ 10 supplementation have been found in those animals fed fish oil-based diets (29), but effects of CoQ 10 supplementation of virgin olive oilbased diets are not so clear. Nevertheless, other studies in rodents have reported that CoQ 10 supplementation with daily doses ranging from 10 to 370 mg/kg in combination with standard diets has no effect on longevity (30,31,54,55), although treatments did not start from weaning in most of these studies (30,31,54). To test if CoQ 10 effects on life span are always present regardless the dietary context, CoQ 10 was also added to the other diets in this study. ...
... Some beneficial effects of CoQ 10 supplementation have been found in those animals fed fish oil-based diets (29), but effects of CoQ 10 supplementation of virgin olive oilbased diets are not so clear. Nevertheless, other studies in rodents have reported that CoQ 10 supplementation with daily doses ranging from 10 to 370 mg/kg in combination with standard diets has no effect on longevity (30,31,54,55), although treatments did not start from weaning in most of these studies (30,31,54). To test if CoQ 10 effects on life span are always present regardless the dietary context, CoQ 10 was also added to the other diets in this study. ...
Extending life by delaying the aging process have proven to be the most effective way to fight multiple chronic diseases in elderly adults. Evidence suggests that longevity is inversely related to unsaturation of membrane phospholipids. The present study investigated how different unsaturated dietary fats affect lifespan and cause death in male Wistar rats fed diets based on virgin olive oil (V), sunflower oil (S) or fish oil (F), which were supplemented or not with Coenzyme Q10 (CoQ10). Previous results suggest that individual longevity and survival probability at different ages may be modulated by an appropriate dietary fat treatment. Lifelong feeding with V or F diets would reduce death probability compared to feeding with S diet at certain ages, although the effects of V diet would be maintained for most of life. Furthermore, the addition of lower amounts of CoQ10 reduced mortality associated with S diet, but CoQ10 had no effect on survival when combined with virgin olive oil or fish oil. Supplementation with low doses of CoQ10 failed to increase the maximum lifespan potential of rats fed a V or F diet. No clear evidence showing that MUFA, n-3 PUFA or CoQ10 exerted the observed effects by modulating the rate of aging has been found.
... This result might be attributed to the high antioxidant efficacy of CoQ 10 to protect cell integrity against ROS and lipid peroxidation induced by toxic agents [15]. However, the effectiveness of CoQ 10 as a protective role against oxidative injury varies greatly according to the physiological status of animals, health and disease of animals, concentration and period of dietary CoQ 10 supplementation, interaction with other nutrients, etc. [3,11,16]. Thus, there is still a lack of evidence about whether the administration of CoQ 10 to young animals during oxidative stress can affect the antioxidant system, despite the rather wellrecognized antioxidant effects of CoQ 10 in vitro. ...
... On the other hand, contradictory studies concerning the effects of CoQ 10 on antioxidant defense system have been reported [16,37]. Dietary CoQ 10 did not directly affect the changes in antioxidant enzymes including SOD, GPX and CAT as well as in the life span of laboratory rats [16,37]. ...
... On the other hand, contradictory studies concerning the effects of CoQ 10 on antioxidant defense system have been reported [16,37]. Dietary CoQ 10 did not directly affect the changes in antioxidant enzymes including SOD, GPX and CAT as well as in the life span of laboratory rats [16,37]. However, the antioxidant properties of CoQ 10 may be was attributed to potentiating electron transport chain where it plays a crucial role in electron donor and acceptor in the mitochondria of the liver [15]. ...
The study was performed to see the effects of coenzyme Q10 (CoQ10) on blood biochemical components and hepatic antioxidant system in rats exposed to lipopolysaccharide (LPS)-induced toxicity. A total of 24 rats were allocated to four groups: control (CON), 100 mg/kg BW of LPS (LPS), 100 mg of CoQ10/kg BW with LPS (LCQI) and 300 mg of CoQ10/kg BW with LPS (LCQII). The LPS and LCQI groups showed a significant (P<0.05) increase in the relative spleen weight compared with the CON group without affecting body and liver weights. The blood alanine aminotransferase (ALT) level in the LPS group was significantly (P<0.05) greater than that in the CON group, while supplementation with 100 or 300 mg CoQ10 to rats injected with LPS normalized the ALT level in the CON group. In antioxidant systems, the LPS group showed a significantly (P<0.05) higher mRNA and activity of superoxide dismutase (SOD) than the CON group. The supplementation with CoQ10 to the LPS-treated group normalized the level of SOD, which was comparable to the level of the CON group. Both the mRNA expression and activity of glutathione peroxidase in the LCQI and LCQII groups were higher (P<0.05) than that of the LPS group. However, administration of LPS or CoQ10 unaffected the level of catalase and total antioxidant power. The level of lipid peroxidation in the LCQII group was lower (P<0.05) than that in the LPS group. In conclusion, CoQ10 exerted its favorable effect against liver damage by modulation of antioxidant enzymes in LPS treated rats.
... The principal aim of this study was to investigate the effect of long-term supplementation of CoQ 10 on the level of oxidative stress by measuring post-translational protein modifications in some of the tissues of the rat as the plasma and the brain. Although not known to increase life span of any laboratory mammalian model including that of rodents [24,32,35], there has been widespread usage of the molecule as an over-the-counter supplement due to its perceived role as an antioxidant. Though there has been no increasing evidence on possible pro-oxidant role of the molecule [6,7], some concerns have been raised that necessitate more research in this area to address these issues. ...
... It is possible that the tissue-specific response may be caused by tissue-specific incorporation of the CoQ 10 following supplementation. It has been reported that while the level of CoQ 10 increased in the plasma (and other tissues) following supplementation [21,22,24], reports on its level in the whole brain homogenate have been controversial. In case of the rat with a similar supplementation regime as applied in this study, there was statistically significant augmentation of CoQ 10 in both the homogenate as well as in the mitochondria of the brain tissue [21]. ...
... Similar report on increased level of CoQ 10 in the rat cerebral cortex mitochondria following supplementation with it has been observed by Matthews et al. [25]. However, this is contrary to the report from mice [22,24] where unlike other tissues, no significant increase in either the brain homogenate or mitochondria following augmentation with a range of dosage of CoQ 10 were observed. Such differences in the reports in Kwong et al. [21] versus Kamzalov et al. [22] and Sohal et al. [24] from the brain tissue may be due to various factors as difference in the amount and regime of CoQ 10 administration, tissue processing, animal husbandry, strain and/or species-specific differences. ...
Background
Two series of 4-benzylidene-6-(4-methyl-phenyl)-4,5-dihydropyridazin-(2H)-one compounds (3a-e) and 4-benzylidene-6-(4-chloro-phenyl)-4,5-dihydropyridazin-(2H)-ones (3f-j) were synthesized and evaluated as anticonvulsant agents.
Methods
Synthesized compounds (3a-3j) were tested against maximum electro shock (MES) and Isoniazid (INH) induced convulsion methods for anticonvulsant activities and neurotoxicity.
Results
In MES induced convulsions, result found that the compounds 3e and 3j exhibited highest anticonvulsant activities. In INH induced convulsions, result was indicated that all the compounds exhibited good anticonvulsant activities., whereas compounds 3d and 3j showed maximum activity. Methyl derivatives were more active than chloro derivatives. Phenytoin sodium (25mg/kg) and sodium vaproate (50mg/kg) were used as reference drugs. All these synthesized pyridazinone compounds (3a-j) did not exhibit any neurotoxicity up to 100 mg/kg dose levels.
Conclusion
All compounds showed good anticonvulsant activities against both MES and INH induced convulsion models. Many such explorations are anticipated in the near future.
... Lipoic acid has shown to decrease lifespan in SAMP8 mice (Farr et al., 2012) despite it was increased in D. melanogaster (Bauer et al., 2004). Exogenous ubiquinone, in the form of coenzyme Q (CoQ) 10, prolonged lifespan in C. elegans (Asencio et al., 2009) but in most of the studies, in both rats and mice, CoQ 10 supplementation was ineffective for increasing lifespan (Lee et al., 2004;Lönnrot et al., 1995;Sohal et al., 2006). Importantly, according to the variety of used CoQ 10 doses (ranged from 10 to 370 mg/Kg per day) and the duration of the different studies, the lack of effects on longevity seems, in many of these studies, not to depend on these conditions. ...
... Again, despite CoQ 10 supplementation was ineffective for increasing lifespan in most of the studies in both rats and mice (Lee et al., 2004;Lönnrot et al., 1995;Sohal et al., 2006), CoQ 10 supplementation would be effective in increasing median life span when it was combined with certain nutritional conditions associated with elevated oxidative stress. In a study on rats comparing isocaloric diets enriched on different lipid profiles by using virgin olive, sunflower or fish oils as a dietary fat source, supplementation with a low dose of CoQ 10 from weaning was able to improve survival in rats receiving a diet with sunflower oil as fat source, increasing median lifespan values. ...
The rise of life expectancy in current societies is not accompanied, to date, by a similar increase in healthspan, which represents a great socio-economic problem. It has been suggested that aging can be manipulated and then, the onset of all age-associated chronic disorders can be delayed because these pathologies share age as primary underlying risk factor. One of the most extended ideas is that aging is consequence of the accumulation of molecular damage. According to the oxidative damage theory, antioxidants should slow down aging, extending lifespan and healthspan. The present review analyzes studies evaluating the effect of dietary antioxidants on lifespan of different aging models and discusses the evidence on favor of their antioxidant activity as anti-aging mechanisms. Moreover, possible causes for differences between the reported results are evaluated.
... 현재까지 연구에 의하면 CoQ10 등과 같은 항산화제의 효 과는 동물의 생리적 상태 및 내외적 스트레스 요인 등 (Shekelle et al., 2003;Sohal et al., 2006;Acosta et al., 2016) 과 더불어 첨가물질의 화학적 형태 역시 매우 중요한 요인 으로 알려져 있다. 특히 친지질성의 항산화 물질은 지질에 유화시키면 닭의 소장에서 흡수가 쉬워 생체 이용률이 현저 히 증가될 수 있다 (Jang et al., 2014) (Bidlack and Tappel, 1973 (Weber et al., 1994;Sohet et al., 2009). ...
... 체 조직에서 SOD, GPX, CAT 등과 같은 항산화 효소들 은 지질과산화를 유발하는 산화적 스트레스 요인들을 제거 하는 작용을 하는 것으로 잘 알려져 있다 (Aebi, 1974;Fridovich, 1974;Tappel, 1978). 본 시험 결과 산란계에서 CoQ10이 항산화 효소들의 발현을 증가시키지는 않았지만 Frei et al.(1990) (Kamzalov et al., 2003 (Kamzalov et al., 2003;Sohal et al., 2006). Sharideh et al.(2020) (Maruyama et al., 1995). ...
... Kidney, together with brain and muscle, has been described as one of the organs with poorest uptake of CoQ 10 [38], a data confirmed by two previous studies of short-term CoQ 10 supplementation in Pdss2 kd/kd mice [17,45]. However, studies of long-term CoQ supplementation in wild-type animals showed accumulation of CoQ in kidney [74]. Our results not only confirm that long-term supplementation is necessary for CoQ 10 to reach target organs, but they also demonstrate that even when CoQ 10 reaches the target organ, not all of its biological functions are restored. ...
... Another alternative hypothesis to explain how CoQ 10 rescues SQOR levels but not respiratory chain enzymes activities is that exogenous CoQ 10 can substitute CoQ 9 (the main specie of CoQ in mice) as electrons acceptor of SQOR, but not in the respiratory chain. However, this hypothesis is unlikely since CoQ 10 supplementation seems to equally increase CoQ 9 and CoQ 10 in kidney of Pdss2 kd/kd , likely via CoQ 10 conversion to CoQ 9 [74]. Importantly, in our study, CoQ supplementation did not affect SQOR transcriptional levels excluding the possibility that CoQ 10 accumulation in liver might trigger liver-kidney signaling pathways that induce Sqor mRNA up-regulation. ...
Nephrotic syndrome (NS), a frequent chronic kidney disease in children and young adults, is the most common phenotype associated with primary coenzyme Q10 (CoQ10) deficiency and is very responsive to CoQ10 supplementation, although the pathomechanism is not clear. Here, using a mouse model of CoQ deficiency-associated NS, we show that long-term oral CoQ10 supplementation prevents kidney failure by rescuing defects of sulfides oxidation and ameliorating oxidative stress, despite only incomplete normalization of kidney CoQ levels and lack of rescue of CoQ-dependent respiratory enzymes activities. Liver and kidney lipidomics, and urine metabolomics analyses, did not show CoQ metabolites. To further demonstrate that sulfides metabolism defects cause oxidative stress in CoQ deficiency, we show that silencing of sulfide quinone oxido-reductase (SQOR) in wild-type HeLa cells leads to similar increases of reactive oxygen species (ROS) observed in HeLa cells depleted of the CoQ biosynthesis regulatory protein COQ8A. While CoQ10 supplementation of COQ8A depleted cells decreases ROS and increases SQOR protein levels, knock-down of SQOR prevents CoQ10 antioxidant effects. We conclude that kidney failure in CoQ deficiency-associated NS is caused by oxidative stress mediated by impaired sulfides oxidation and propose that CoQ supplementation does not significantly increase the kidney pool of CoQ bound to the respiratory supercomplexes, but rather enhances the free pool of CoQ, which stabilizes SQOR protein levels rescuing oxidative stress.
... Agreeing with the results of this study, Leelarungrayub et al. (18) suggested that the 12 d of CoQ 10 supplementation reduces oxidative stress and improves TAC (including proteins and enzymatic and non-enzymatic antioxidant compounds) level and CoQ 10 concentration, within a sample of young swimmers (18) . Altogether, the results of the study by Sohal et al. (32) indicated that, contrary to the present results, supplemental intake of CoQ 10 has no discernable effect on the main antioxidant defenses or prooxidant generation in most tissues of mice (32) . Bloomer et al. (33) indicated that in physically active men and women, 30 d of CoQ 10 supplementation (300 mg/d) increased the reduced serum CoQ 10 , but that increase did not affect exercise performance and resting or exercise-induced measures of oxidative stress. ...
... Agreeing with the results of this study, Leelarungrayub et al. (18) suggested that the 12 d of CoQ 10 supplementation reduces oxidative stress and improves TAC (including proteins and enzymatic and non-enzymatic antioxidant compounds) level and CoQ 10 concentration, within a sample of young swimmers (18) . Altogether, the results of the study by Sohal et al. (32) indicated that, contrary to the present results, supplemental intake of CoQ 10 has no discernable effect on the main antioxidant defenses or prooxidant generation in most tissues of mice (32) . Bloomer et al. (33) indicated that in physically active men and women, 30 d of CoQ 10 supplementation (300 mg/d) increased the reduced serum CoQ 10 , but that increase did not affect exercise performance and resting or exercise-induced measures of oxidative stress. ...
Strenuous physical exercise and hyperthermia may paradoxically induce oxidative stress and adverse effects on myocardial function. The purpose of this study was to investigate the effect of 14-d coenzyme Q 10 (CoQ 10 ) supplementation and pre-cooling on serum creatine kinase-MB (CK-MB), cardiac Troponin I (cTnI), myoglobin (Mb), lactate dehydrogenase (LD), total antioxidant capacity (TAC), lipid peroxidation (LPO) and CoQ 10 concentration in elite swimmers. In total, thirty-six healthy males (mean age 17 ( sd 1) years) were randomly selected and divided into four groups of supplementation, supplementation with pre-cooling, pre-cooling and control. During an eighteen-session protocol in the morning and evening, subjects attended speed and endurance swimming training sessions for 5 km in each session. Blood sampling was done before (two stages) and after (two stages) administration of CoQ 10 and pre-cooling. ANCOVA and repeated measurement tests with Bonferroni post hoc test were used for the statistical analysis of the data. There was no significant statistical difference among groups for the levels of CK-MB, cTnI, Mb, LD, TAC, LPO and CoQ 10 at the presampling (stages 1 and 2) ( P >0·05). However, pre-cooling and control groups show a significant increase in the levels of CK-MB, cTnI, Mb, LD and LPO compared with the supplementation and supplementation with pre-cooling groups in the post-sampling (stages 1 and 2) ( P <0·05), except for the TAC and CoQ 10 . Consequently, CoQ 10 supplementation prevents adverse changes of myocardial damage and oxidative stress during swimming competition phase. Meanwhile, the pre-cooling strategy individually has no desired effect on the levels of CK-MB, cTnI, Mb, LD, LPO, TAC and CoQ 10 .
... Coenzyme Q10 (CoQ10) is a redox component of the respiratory chain that contributes to the regulation of energy metabolism and cell death (7,8). In addition, CoQ10 has been confirmed to be the only endogenous antioxidant that inhibits lipid peroxidation and provides protection against oxidative stress injury to mitochondrial proteins and DNA (9). Proteins in subcellular membranes can be uncoupled by CoQ10 as a cofactor, but its main role is to scavenge reactive oxygen species (ROS) from mitochondria and other biological membranes and to act as an antioxidant. ...
Coenzyme Q10 (CoQ10) is a potent antioxidant that is implicated in the inhibition of osteoclastogenesis, but the underlying mechanism has not been determined. We explored the underlying molecular mechanisms involved in this process. RAW264.7 cells received receptor activator of NF-κB ligand (RANKL) and CoQ10, after which the differentiation and viability of osteoclasts were assessed. After the cells were treated with CoQ10 and/or H2O2 and RANKL, the levels of reactive oxygen species (ROS) and proteins involved in the PI3K/AKT/mTOR and MAPK pathways and autophagy were tested. Moreover, after the cells were pretreated with or without inhibitors of the two pathways or with the mitophagy agonist, the levels of autophagy-related proteins and osteoclast markers were measured. CoQ10 significantly decreased the number of TRAP-positive cells and the level of ROS but had no significant impact on cell viability. The relative phosphorylation levels of PI3K, AKT, mTOR, ERK, and p38 were significantly reduced, but the levels of FOXO3/LC3/Beclin1 were significantly augmented. Moreover, the levels of FOXO3/LC3/Beclin1 were significantly increased by the inhibitors and mitophagy agonist, while the levels of osteoclast markers showed the opposite results. Our data showed that CoQ10 prevented RANKL-induced osteoclastogenesis by promoting autophagy via inactivation of the PI3K/AKT/mTOR and MAPK pathways in RAW264.7 cells.
... Regarding the Q10 levels, we revealed a nonsignificant elevation among FA patients compared to controls (p = 0.064), with the difference becoming even less significant when considering Q10 supplementation (p = 0.160). The study's findings underscore the need to consider Q10 supplementation history in FA, as it notably influences gene expression related to COX subunits and stress response pathways, according to a mouse study [59]. Although Q10 levels are elevated, potentially as a compensatory mechanism, this increase does not appear to significantly affect the activities of other ETC complexes. ...
This study presents an in-depth analysis of mitochondrial enzyme activities in Friedreich's ataxia (FA) patients, focusing on the Electron Transport Chain complexes I, II, and IV, the Krebs Cycle enzyme Citrate Synthase, and Coenzyme Q10 levels. It examines a cohort of 34 FA patients, comparing their mitochondrial enzyme activities and clinical parameters, including disease duration and cardiac markers, with those of 17 healthy controls. The findings reveal marked reductions in complexes II and, specifically, IV, highlighting mitochondrial impairment in FA. Additionally, elevated Neurofilament Light Chain levels and cardiomarkers were observed in FA patients. This research enhances our understanding of FA pathophysiology and suggests potential biomarkers for monitoring disease progression. The study underscores the need for further clinical trials to validate these findings, emphasizing the critical role of mitochondrial dysfunction in FA assessment and treatment.
... Previous studies reported that CoQ10 supplementation can lead to an increment in its levels in the mitochondria of the brain, heart, skeletal muscles, liver, and kidneys of rats [14]. Moreover, according to previously published papers, supplementary CoQ10 raised the levels of CoQ10 in the human plasma and cells such as platelets and white blood cells [2,15]. ...
Coenzyme Q10 (CoQ10), commonly known as ubiquinone, is a vitamin-like component generated in mitochondrial inner membranes. This molecule is detected broadly in different parts of the human body in various quantities. This molecule can be absorbed by the digestive system from various nutritional sources as supplements. CoQ10 exists in three states: in a of reduced form (ubiquinol), in a semiquinone radical form, and in oxidized ubiquinone form in different organs of the body, playing a crucial role in electron transportation and contributing to energy metabolism and oxygen utilization, especially in the musculoskeletal and nervous systems. Since the early 1980s, research about CoQ10 has become the interest for two reasons. First, CoQ10 deficiency has been found to have a link with cardiovascular, neurologic, and cancer disorders. Second, this molecule has an antioxidant and free-radical scavenger nature. Since then, several investigations have indicated that the drug may benefit patients with cardiovascular, neuromuscular, and neurodegenerative illnesses. CoQ10 may protect the neurological system from degeneration and degradation due to its antioxidant and energy-regulating activity in mitochondria. This agent has shown its efficacy in preventing and treating neurological diseases such as migraine, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and Friedreich’s ataxia. This study reviews the literature to highlight this agent’s potential therapeutic effects in the mentioned neurological disorders.
... Similar beneficial effects have been obtained in cancer and Alzheimer's disease (AD), in whose pathogenesis OS plays a predominant role [60,61]. Although beneficial, lifelong supplementation with CoQ 10 may also be deleterious [92][93][94]. In this respect, results from a study designed to address CoQ 10 administration only later in life showed that old mice subjected to a high CoQ 10 diet displayed reduced OS in various tissues and were more efficient in performing the Morris water maze test compared to the untreated counterpart [95]. ...
Cellular senescence is an irreversible state of cell cycle arrest occurring in response to stressful stimuli, such as telomere attrition, DNA damage, reactive oxygen species, and oncogenic proteins. Although beneficial and protective in several physiological processes, an excessive senescent cell burden has been involved in various pathological conditions including aging, tissue dysfunction and chronic diseases. Oxidative stress (OS) can drive senescence due to a loss of balance between pro-oxidant stimuli and antioxidant defences. Therefore, the identification and characterization of antioxidant compounds capable of preventing or counteracting the senescent phenotype is of major interest. However, despite the considerable number of studies, a comprehensive overview of the main antioxidant molecules capable of counteracting OS-induced senescence is still lacking. Here, besides a brief description of the molecular mechanisms implicated in OS-mediated aging, we review and discuss the role of enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur compounds, nitrogen non-protein molecules, minerals, flavonoids, and non-flavonoids as antioxidant compounds with an anti-aging potential, therefore offering insights into innovative lifespan-extending approaches.
... FSP1 catalyzes the NAD(P)H-dependent reduction of coenzyme Q 10 (CoQ 10 , also known as ubiquinone) to ubiquinol (CoQ10H 2 ), which is a potent antioxidant that attenuates lipid peroxidation [59][60][61]. CoQ 10 is a lipophilic molecule present in every cell membrane, especially in the inner mitochondrial membrane, where it is responsible for transporting electrons from complexes I and II to complex III [62,63]. CoQ 10 deficiency has been linked to many diseases, including encephalomyopathy, cerebellar ataxia, ischemic heart disease, and metabolic syndrome [64,65]. ...
Ferroptosis is a type of programmed cell death caused by phospholipid peroxidation that has been implicated as a mechanism in several diseases resulting from ischemic-reperfusion injury. Most recently, ferroptosis has been identified as a possible key injury mechanism in neonatal hypoxic-ischemic brain injury (HIBI). This review summarizes the current literature regarding the different ferroptotic pathways, how they may be activated after neonatal HIBI, and which current or investigative interventions may attenuate ferroptotic cell death associated with neonatal HIBI.
... Furthermore, CoQ10 supplement might directly enhance antioxidant defense system via potentiating electron transport chain in liver mitochondria (Novoselova et al., 2009). Instead, modifying the expression of antioxidant enzymes in animals insists that dietary CoQ10 directly affects the expression of antioxidant enzymes in tissues (Sohal et al., 2006 andNovoselova et al., 2009). ...
... However, CoQ10 possesses utility beyond facilitation of oxidative phosphorylation, as it can transition between its fully oxidized state (ubiquinone), partially reduced free radical state (ubisemiquinone), and fully reduced state (ubiquinol). CoQ10 is thus an excellent antioxidant and free radical scavenger, thereby performing crucial functions to support not only mitochondrial health but the health of the cell as a whole [43]. Genetic CoQ10 deficiency manifests heterogeneously as a diverse range of symptoms, reflecting the universal importance of the molecule throughout the body [44], though many of these symptoms can be effectively treated with oral CoQ10 supplements [45]. ...
Introduction:
The death of retinal neurons causes permanent and irreversible vision loss, severely impairing quality of life. By targeting toxic conditions which cause neuronal death, such as oxidative stress and ischaemia, neuroprotective agents provide utility in slowing or stopping sight loss resulting from eye disease. While clinical use of neuroprotectants remains limited, there are a few promising compounds presently in early clinical trials (pre-phase III) which may fulfil exciting new therapeutic roles. Search terms relating to neuroprotection and eye disease were used on ClinicalTrials.gov to identify relevant compounds.
Areas covered:
This review focuses research supporting neuroprotective compounds in eye diseases which range from preclinical stages to phase II, as listed on the clinicaltrials.gov database. The compounds under discussion, namely NGF, Saffron, Ubiquinone, and CNTF, are discussed in terms of potential clinical applications in the near future.
Expert opinion:
Until recently, the major challenge in neuroprotection research has been the successful translation from basic research to the clinic. A number of potential neuroprotective molecules have progressed to ophthalmology clinical trials in the last few years, with defined mechanisms of action - saffron and CoQ10 - targeting the mitochondria, and both CNTF and NGF showing anti-apoptotic effects. Enhancements in trial design and choice of patient cohorts in these chronic diseases using proof-of-concept trials with enriched patient populations and surrogate endpoints should increase drug development speed. A further important consideration is optimising drug delivery approaches with improvements in individualised management and patient compliance. Progress in all these areas means that neuroprotective strategies have a much improved chance nowadays of translational success.
... The physiological oxidoreductase properties of CoQ10 allow it to act as an electron transporter between NADH dehydrogenase and succinate dehydrogenase, and from succinate dehydrogenase to the cytochrome bc complex [87]. Selectively targeting CoQ10 to the mitochondria is limited by high lipophilicity, large molecular weight, and poor aqueous solubility; consequently, clinical trials often administer high doses (≥200 mg/day) to support prophylactic outcomes [88,89]. To overcome this, a TPP+ moiety of ubiquinol (mitoquinone [MitoQ]) comprised of a 10-carbon alkyl chain was developed by Robin Smith and Michael Murphy [90,91]. ...
Exercise simultaneously incites beneficial (e.g., signal) and harming (e.g., damage to macromolecules) effects, likely through the generation of reactive oxygen and nitrogen species (RONS) and downstream changes to redox homeostasis. Given the link between nuclear DNA damage and human longevity/pathology, research attempting to modulate DNA damage and restore redox homeostasis through non-selective pleiotropic antioxidants has yielded mixed results. Furthermore, until recently the role of oxidative modifications to mitochondrial DNA (mtDNA) in the context of exercising humans has largely been ignored. The development of antioxidant compounds which specifically target the mitochondria has unveiled a number of exciting avenues of exploration which allow for more precise discernment of the pathways involved with the generation of RONS and mitochondrial oxidative stress. Thus, the primary function of this review, and indeed its novel feature, is to highlight the potential roles of mitochondria-targeted antioxidants on perturbations to mitochondrial oxidative stress and the implications for exercise, with special focus on mtDNA damage. A brief synopsis of the current literature addressing the sources of mitochondrial superoxide and hydrogen peroxide, and available mitochondria-targeted antioxidants is also discussed.
... One such therapeutic compound is the orally-available mitochondrial-targeted coenzyme Q10, termed Mitoquinone (MitoQ) [20]. Accumulation of coenzyme Q10 within mitochondria is limited by high lipophilicity, large molecular weight, and poor aqueous solubility, and as a result clinical trials often administer high doses [21]. Conversely, a triphenylphosphonium cation enables MitoQ to accumulate in mitochondria at approximately 100-1000 times greater than non-targeted derivatives [22]. ...
High-intensity exercise damages mitochondrial DNA (mtDNA) in skeletal muscle. Whether MitoQ - a redox active mitochondrial targeted quinone - can reduce exercise-induced mtDNA damage is unknown. In a double blind, randomized, placebo-controlled design, twenty-four healthy male participants consisting of two groups (placebo; n=12, MitoQ; n=12) performed an exercise trial of 4 x 4-minute bouts at 90-95% of heart rate max. Participants completed an acute (20mg MitoQ or placebo 1-hour pre-exercise) and chronic (21 days of supplementation) phase. Blood and skeletal muscle were sampled immediately pre- and post-exercise and analysed for nuclear and mtDNA damage, lipid hydroperoxides, lipid soluble antioxidants, and the ascorbyl free radical. Exercise significantly increased nuclear and mtDNA damage across lymphocytes and muscle (P < 0.05), which was accompanied with changes in lipid hydroperoxides, ascorbyl free radical, and α-tocopherol (P < 0.05). Acute MitoQ treatment failed to impact any biomarker likely due to insufficient initial bioavailability. However, chronic MitoQ treatment attenuated nuclear (P < 0.05) and mtDNA damage in lymphocytes and muscle tissue (P < 0.05). Our work is the first to show a protective effect of chronic MitoQ supplementation on the mitochondrial and nuclear genomes in lymphocytes and human muscle tissue following exercise, which is important for genome stability.
... However, CoQ10 is poorly absorbed and its ability to accumulate in the mitochondria it limited by high lipophilicity, large molecular weight and poor aqueous solubility (Greenberg and Frishman 1990). Therefore, high doses (> 200 mg) are usually used and this may limit clinical application, and explain the limited effect on the lifespan of mice (Sohal et al. 2006). ...
PurposeExcess production of reactive oxygen species (ROS) from the mitochondria can promote mitochondrial dysfunction and has been implicated in the development of a range of chronic diseases. As such there is interest in whether mitochondrial-targeted antioxidant supplementation can attenuate mitochondrial-associated oxidative stress. We investigated the effect of MitoQ and CoQ10 supplementation on oxidative stress and skeletal muscle mitochondrial ROS levels and function in healthy middle-aged men.Methods
Skeletal muscle and blood samples were collected from twenty men (50 ± 1 y) before and following six weeks of daily supplementation with MitoQ (20 mg) or CoQ10 (200 mg). High-resolution respirometry was used to determine mitochondrial respiration and H2O2 levels, markers of mitochondrial mass and antioxidant defences were measured in muscle samples and oxidative stress markers in urine and blood samples.ResultsBoth MitoQ and CoQ10 supplementation suppressed mitochondrial net H2O2 levels during leak respiration, while MitoQ also elevated muscle catalase expression. However, neither supplement altered urine F2-isoprostanes nor plasma TBARS levels. Neither MitoQ nor CoQ10 supplementation had a significant impact on mitochondrial respiration or mitochondrial density markers (citrate synthase, mtDNA/nDNA, PPARGC1A, OXPHOS expression).Conclusion
Our results suggest that neither MitoQ and CoQ10 supplements impact mitochondrial function, but both can mildly suppress mitochondrial ROS levels in healthy middle-aged men, with some indication that MitoQ may be more effective than CoQ10.
... In the liver the CoQ pools are much smaller with~250 pmol CoQ 9 and~6 pmol CoQ 10 per mg protein (Fig. 6c). These values are consistent with the previously reported values [25,26]. Interestingly the CoQ 9 /CoQ 10 ratio varied significantly between organs, being~10 in heart and~42 in liver (Fig. 6d). ...
Coenzyme Q (CoQ) is an essential cofactor, primarily found in the mitochondrial inner membrane where it functions as an electron carrier in the respiratory chain, and a lipophilic antioxidant. The redox state of the CoQ pool is the ratio of its oxidised (ubiquinone) and reduced (ubiquinol) forms, and is a key indicator of mitochondrial bioenergetic and antioxidant status. However, the role of CoQ redox state in vivo is poorly understood, because determining its value is technically challenging due to redox changes during isolation, extraction and analysis. To address these problems, we have developed a sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay that enables us to extract and analyse both the CoQ redox state and the magnitude of the CoQ pool with negligible changes to redox state from small amounts of tissue. This will enable the physiological and pathophysiological roles of the CoQ redox state to be investigated in vivo.
... 143 These and other findings led to the synthesis of the mitochondria-targeted ubiquinone (MitoQ), which selectively targets mitochondria to increase the accumulation of CoQ 10 and reduce mitochondrial oxidative stress. 142,144 In a small double-blind randomized crossover control trial of older adult humans with impaired endothelial function, 6 weeks of oral supplementation with MitoQ mitigated mitochondrial ROS-related suppression of endothelial function and improved brachial arterial flow. 145 ...
... [12] The rate was determined as n moles of TBARS formed/mg of protein using a molar extinction coefficient of 1.56 × 10 5 M −1 cm −1 . The protein carbonyl (PC) content was measured using dinitrophenylhydrazine as described by Sohal et al. [17] Histopathological examination ...
Background: Tacrolimus is a known immunosuppressive drug used widely for organ transplantation, but its nephrotoxicity mechanism is still unclear. Objectives: The present study investigates the protective efficacy of Bacopa monnieri (BM), against tacrolimus‑induced nephrotoxicity in rats. Materials and Methods: Group 1 (control group); administered orally with normal saline for 30 days; Group 2 (BM extract treated group); Group 3 (tacrolimus‑treated group); and Group 4; (tacrolimus plus BM extract treated group). Tacrolimus‑treated rats received 1 mg/kg body weight of tacrolimus intraperitoneally for 30 days, and BM‑pretreated rats were administered with the dose of 200 mg/kg orally by gavage once a day for 30 days. Results: Tacrolimus‑induced nephrotoxicity was assessed biochemically and histopathologically. Pretreatment with BM has shown to possess a significant protective effect against tacrolimus‑induced kidney functions regarding urea, creatinine, and albumin levels, respectively. The creatinine, mitochondrial lipid peroxidation (thiobarbituric acid reactive substances), and protein carbonyl levels were significantly increased dramatically, and however, the total proteins, albumin, glutathione, superoxide dismutase, and glutathione peroxidase were decreased when pretreated with tacrolimus. The nephroprotective efficacy of the BM extract was further evident by histopathological analysis and DNA fragmentation. Conclusion: The outcome of this study indicates that BM extracts exerted protection against tacrolimus‑induced kidney toxicity.
Key words: Antioxidant activity, Bacopa monnieri, DNA fragmentation, nephrotoxicity, tacrolimus
... Furthermore, in studies of rats and mice, longterm CoQ10 treatment in adulthood was observed to have no effect on their lifespan (23) . Our results did not show any significant effect of CoQ10 supplementation on body weight. ...
... It is the only lipid-soluble antioxidant synthesized endogenously. Coenzyme Q10 acts directly by protecting cellular components from free radicals and indirectly via regenerating other antioxidants such as α-tocopherol and ascorbate [10]. It may induce some genes, and some of the effects of exogenously administered CoQ10 may be due to this property. ...
Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder associated with aging. This study aimed to explore the modulatory effects of Coenzyme Q10 (CoQ10) (10 mg mg/kg., b.w.) and [Cu (I)-(nicotinic acid) 2] 1 Cl-complex (Cu-N complex) (400 µg/kg., b.w.) on aluminium chloride (AlCl3)-100 mg/kg b.w.) induced rat model of AD. Our results revealed that oral administration of AlCl3 for 42 days significantly elevated the levels of brain myeloperoxidase(MPO) activity and IL-1β levels, while Catalase and Na+/ K+ ATPase activity were markedly decreased. Plasma ferric reducing ability of plasma (ferric reducing/antioxidant power (FRAP) and superoxide dismutase (SOD)levels were noticeably decreased but Aspartate Transaminase (AST) concentrations were significantly increased, confirming that abnormal inflammatory response is associated with AD. Treatment by CoQ10 and Cu-Ncomplex restored the above mentioned parameters to about normal levels comparable to those of AD, indicating that IL-1β and Na+ / K+ ATPase activity may be considered as new biomarkers for AD. Histopathological and comet assay examinations confirmed the neuroprotective effect of CoQ10and Cu-N complex. The present data advocate the possible beneficial effect of CoQ10 and Cu-N complex protecting the cells against hepatocellular damage and as therapeutic modality for Alzheimer's disease via its anti-inflammatory/antioxidant mechanism.
... However, Sohal and Forster showed that CoQ 10 dietary supplementation in rodents was able to change the subcellular localization of CoQ, increasing the mitochondrial content of both coenzymes in various mitochondria-rich tissues, such as liver, heart, and skeletal muscle [72]. In another study, the same authors confirmed that skeletal muscle increase in CoQ 10 following supplementation was the lowest in all analyzed tissues [73]. In the present study, we verified that the use of orally administered reduced CoQ 10 did not provide any significant improvement in tissue uptake, showing results in line with previous reports where ubiquinone was used as active substance. ...
Aging skeletal muscles are characterized by a progressive decline in muscle mass and muscular strength. Such muscular dysfunctions are usually associated with structural and functional alterations of skeletal muscle mitochondria. The senescence-accelerated mouse-prone 8 (SAMP8) model, characterized by premature aging and high degree of oxidative stress, was used to investigate whether a combined intervention with mild physical exercise and ubiquinol supplementation was able to improve mitochondrial function and preserve skeletal muscle health during aging. 5-month-old SAMP8 mice, in a presarcopenia phase, have been randomly divided into 4 groups ( n=10 ): untreated controls and mice treated for two months with either physical exercise (0.5 km/h, on a 5% inclination, for 30 min, 5/7 days per week), ubiquinol 10 (500 mg/kg/day), or a combination of exercise and ubiquinol. Two months of physical exercise significantly increased mitochondrial damage in the muscles of exercised mice when compared to controls. On the contrary, ubiquinol and physical exercise combination significantly improved the overall status of the skeletal muscle, preserving mitochondrial ultrastructure and limiting mitochondrial depolarization induced by physical exercise alone. Accordingly, combination treatment while promoting mitochondrial biogenesis lowered autophagy and caspase 3-dependent apoptosis. In conclusion, the present study shows that ubiquinol supplementation counteracts the deleterious effects of physical exercise-derived ROS improving mitochondrial functionality in an oxidative stress model, such as SAMP8 in the presarcopenia phase.
... Protein carbonyl content was measured using dinitrophenylhydrazine (DNPH) as described by Sohal et al. [21]. The difference in the absorbance between DNPH treated and HCl treated sample is determined and expressed as nmoles of carbonyl groups per mg of protein, using extinction coefficient of 22 mM −1 cm −1 . ...
Tacrolimus (TAC) is used sporadically as an immunosuppressive agent for organ transplantation, but its clinical used is limited due to its marked nephrotoxicity. Ocimum basilicum L. (Lamiaceae) (OB) had been shown to possess antioxidant, anti-inflammatory and nephroprotective activity, and effective at improving renal inflammation and glomerular. In our study, we aim to evaluate the efficacy of the OB against TAC-induced mitochondrial nephrotoxicity in CD1 mice. Mice were randomly divided into four groups. Group 1 (control group); administered orally with normal saline (1 mL/kg) for two weeks; Group 2 (OB extract treated-group) (500 mg/kg b.wt) gavaged once/day for two weeks; Group 3 (TAC-treated group) (3 mg/kg b.wt, administered ip once a day for two weeks); and Group 4; (TAC plus OB extract treated-group). Tacrolimus-induced nephrotoxicity was assessed biochemically and histopathologically. The OB extract was high in phenolic content (50.3 mg/g of gallic acid equivalent), total flavonoids (14.5 mg/g CE equivalent). The potential antioxidant efficacy of the extract (IC50) was 24.5 μg/mL. OB pretreatment significantly improved the TAC-induced changes in biochemical markers of nephrotoxicity for instance blood urea nitrogen (BUN), creatinine, total protein, and albumin (P < 0.01, when compared with TAC treated group). Also, it significantly restored the increase activities of TBARS, protein carbonyl (PC) (P < 0.001, when compared to healthy control group) and decreased activities of nonprotein thiol (NP–SH) levels, Mn-superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx) antioxidants of mitochondria. The nephroprotective efficacy of the OB leaves extract was further evident by histopathological analysis together with the PCNA-ir and Bcl2. The upshot of the present study revealed that the OB possessed significant antioxidant and nephroprotective activity and had a preventive effect on the biochemical alterations and histological changes in TAC-treated mice.
... It is the only lipid-soluble antioxidant synthesized endogenously. Coenzyme Q10 acts directly by protecting cellular components from free radicals and indirectly via regenerating other antioxidants such as α-tocopherol and ascorbate [10]. It may induce some genes, and some of the effects of exogenously administered CoQ10 may be due to this property. ...
Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder associated with aging. This study aimed to explore the modulatory effects of Coenzyme Q10 (CoQ10) (10 mg mg/kg., b.w.) and [Cu (I)-(nicotinic acid) 2] 1 Cl-complex (Cu-N complex) (400 µg/kg., b.w.) on aluminium chloride (AlCl3)-100 mg/kg b.w.) induced rat model of AD. Our results revealed that oral administration of AlCl3 for 42 days significantly elevated the levels of brain myeloperoxidase(MPO) activity and IL-1β levels, while Catalase and Na+/ K+ ATPase activity were markedly decreased. Plasma ferric reducing ability of plasma (ferric reducing/antioxidant power (FRAP) and superoxide dismutase (SOD)levels were noticeably decreased but Aspartate Transaminase (AST) concentrations were significantly increased, confirming that abnormal inflammatory response is associated with AD. Treatment by CoQ10 and Cu-Ncomplex restored the above mentioned parameters to about normal levels comparable to those of AD, indicating that IL-1β and Na+ / K+ ATPase activity may be considered as new biomarkers for AD. Histopathological and comet assay examinations confirmed the neuroprotective effect of CoQ10and Cu-N complex. The present data advocate the possible beneficial effect of CoQ10 and Cu-N complex protecting the cells against hepatocellular damage and as therapeutic modality for Alzheimer's disease via its anti-inflammatory/antioxidant mechanism.
... In cells, CoQ is located in the middle of the phospholipid bilayer of various membranes; however, the relative amount varies in different organelles [14]. ...
This systematic review is aimed to identify, evaluate and summarize the role of oral Coenzyme Q10 supplementation in prevention and treatment of cardiovascular diseases (CVD). CoQ10 is concentrated primarily in the cellular mitochondria where it functions as a co-factor transferring electrons from Complex I to Complex II, III ultimately resulting in the formation of energy in the form of ATP. Coenzyme Q10 an endogenous antioxidant declines in our body because of various factors like aging, diseases and use of certain drugs like statins, beta-blockers which exacerbate its deficiency. Deficiency of this important endogenous antioxidant CoQ10 results in energy depleted state. Published data and research have suggested that Coenzyme Q10 an endogenous antioxidant has a potential for being used in the prevention and treatment of CVDs, in particular in Heart failure and Ischemic heart disease. Supplementation with CoQ10 not only corrects the deficiency of CoQ10 by improving the circulating levels of CoQ10 but also shows a significant improvement in various parameters like ejection fraction, NYHA class, symptom score and survival rate. Being a natural substance with low toxicity.
... This enhancing effect is probably connected with higher retention of coenzyme Q10 in cells when loaded in polymeric micelles (Liu et al., 2011). These observations, together with the conclusions by Sohal et al. (Sohal et al., 2006) that the dietary supplementation of coenzyme Q10 is insufficient to elevate the antioxidative defenses in tissues, suggest that topical delivery with good penetrability may be more effi-cient in replenishing the bioactivity of coenzyme Q10 in human skin. ...
Nanosized materials offer promising strategy for topical drug delivery due to their enhancing effect on drug percutaneous transport across the stratum corneum barrier. In this work, polymeric micelles made from hydrophobized hyaluronic acid (HA) were probed for skin delivery. Compared to non-polymeric micelle solutions containing similar drug amount, in vitro skin penetration analysis indicated 3 times larger deposition of drug in the epidermis and 6 times larger drug deposition in the dermis after 5 hours of topical treatment in Franz diffusion cells. The drug deposition was further increased with prolonged time of topical treatment. Laser confocal microscopy revealed the accumulation of both, the HA forming the vehicle and the payload, in the epidermis and dermis. Although fluorescent labeling of the HA would suggest co-transport of the HA and the drug, loading FRET pair dyes in the micellar core clearly demonstrated gradual micelle disruption with increasing skin depth. Transcellular penetration was the predominant pathway for the loaded drug. The HA polymeric micelles also demonstrated increased bioactivity of loaded compound in vitro and in vivo. In addition, the loaded micelles were found to be stable in cream formulations and thus they have great potential for topical applications for cosmetic and pharmaceutical purposes.
... 238 However, addition of coenzyme Q10 does not affect the respiratory chain activities, superoxide generation, and antioxidants in C57BL/6 mice. 239 Coenzyme Q10 may attenuate the aging defect in heart mitochondria. ...
Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is approximate to 50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.
Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid sidechain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) and in several other cellular processes. In fact, CoQ appears to be central to the redox balance of the cell. Remarkably, its structure and properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox active molecule in the ETC and other enzymatic systems, its role as a pro-oxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.
Cutaneous melanoma is the deadliest malignant skin cancer due to its poor prognosis, rapid local growth, and high metastasis. Transdermal administration for local drug delivery would be one of the most appropriate therapy regimens. However, promoting drug penetration into deep tumor tissue and maintaining the balance of redox homeostasis during the antitumor treatment to inhibit melanoma progression remains a great challenge in melanoma treatment. Herein, non‐invasive transdermal delivery systems are reported for melanoma treatment, which is composed of biocompatible hydrogel and penetrating nanocarriers. Highly penetrating nanocarriers can co‐deliver paclitaxel and coenzyme Q10 for inhibiting melanoma and reducing side effects, which are attributed to drug encapsulation, deep tissue penetration, high cellular uptake, and organelle targeting. More importantly, biocompatible hydrogels serve as nanocarriers platforms for melanoma location and transdermal delivery. This hierarchical nanoparticle‐hydrogel system achieves high‐efficiency non‐invasive transdermal delivery for inhibiting melanoma, blocking adverse effects, and restraining melanoma development.
Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).
Cyclophosphamide (CTX) has been broadly used in the clinic for the treatment of autoimmune disorders and ovarian cancer. The process of chemotherapy has significant toxicity in the reproductive system as it has detrimental effects on folliculogenesis, which leads to an irreversible premature ovarian failure (POF). Coenzyme Q10 (CoQ10) has positive impacts on the reproductive system due to its antioxidant properties, protecting the cells from free-radical oxidative damage and apoptosis. However, little is known about the possible synergistic effect of CTX and CoQ10 on the expression of genes involved in folliculogenesis, such as proliferation cell nuclear antigen (PCNA) and follicle-stimulating hormone receptor (FSHR). A total of 32 NMRI mice were applied and divided into four groups, including healthy control, CTX, CTX + CoQ10, and CoQ10 groups. The effects of CoQ10 on CTX-induced ovarian injury and folliculogenesis were examined by histopathological and real-time quantitative reverse transcription-polymerase chain reaction analyses. The rates of fertilization (in vitro fertilization), embryo development, as well as the level of reactive oxygen species (ROS) in metaphase II (MII) mouse oocytes after PMSG/HCC treatment were also assessed. Results showed that the treatment with CTX decreased the mRNA expression of PCNA and FSHR, IVF rate, and embryo development whereas the application of CoQ10 successfully reversed those factors. CoQ10 administration significantly enhanced histological morphology and decreased ROS levels and the number of atretic follicles in the ovary of CTX-treated mice. In conclusion, it seems that the protective effect of CoQ10 is exerted via the antioxidant and proliferative properties of this substance on CTX-induced ovarian damage.
Supplement use remains common in USA, primarily due to public interest in improving health and well-being. Vitamins, minerals, and macronutrient supplement formulations remain some of the most commonly used; however, few have been systematically studied regarding their role in promoting cardiovascular health. Fairly consistently, diets rich in many of these compounds have been found in epidemiologic studies to confer benefit; however, existing interventional or cohort studies generally have failed to find pervasive evidence of benefit with some exception. Notably, the heterogeneity of different compounds is paralleled by the heterogeneity of studies, with differing formulations, dosing, populations studied, and outcomes limiting interpretation and generalizability. Still, both consumer and research interest remain strong in evaluating the impact these supplements have on improving cardiovascular health. This chapter will outline existing literature for some of the most commonly used supplements, including major limitations—and promise—for the use of these supplements in populations with average and elevated risk for cardiovascular disease and outcomes.
Significance:
During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumour suppressor.
Critical issues:
Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans.
Future directions:
Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Pre-clinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials.
Coenzyme Q10 (CoQ10) has been reported to improve bone density and the number of trabeculae in postmenopausal osteoporosis, but the mechanism remains to be elucidated. We aimed to investigate the effects of CoQ10 on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and the underlying molecular mechanisms. RAW264.7 cells were treated with different concentrations of RANKL to differentiate into osteoclasts, and then these cells were treated with different concentrations of CoQ10 with or without H2 O2 . Tartrate-resistant acid phosphatase staining was performed to detect osteoclasts. Cell viability was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, cell apoptosis was examined by flow cytometry, and the effects of CoQ10 on protein and messenger RNA expression of mitochondrial apoptosis-associated proteins and osteoclast marker proteins were measured by quantitative reverse transcription polymerase chain reaction and western blot, respectively. Furthermore, enzyme-linked immunosorbent assay was conducted to analyze the activities of malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). RANKL significantly induced osteoclastogenesis in RAW264.7 cells, with the greatest efficiency at 50 ng/ml. CoQ10 had no significant effects on cell viability but it significantly increased the percentages of cell apoptosis. Mechanically, CoQ10 statistically decreased the levels of Bcl-2 and cytochrome C in mitochondria and upregulated the levels of Bax, cleaved caspase 3, and cytochrome C in the cytoplasm. Moreover, CoQ10 significantly decreased RANKL-induced osteoclastogenesis regardless of exposure to H2 O2 . In addition, CoQ10 statistically reduced MDA activity and elevated the activities of SOD and CAT, as well as the expression of oxidative stress-related proteins. CoQ10 may inhibit RANKL-induced osteoclastogenesis by regulation of mitochondrial apoptosis and oxidative stress in RAW264.7 cells.
Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.
With the increasing global burden of glaucoma-caused blindness there is a significant need to develop therapies that both enable early detection of retinal neurodegeneration, and help protect cells from the neurodegenerative processes of glaucoma. In this chapter, we discuss potential neuroprotective agents that are present naturally and examine their role and suitability as therapies in glaucoma. These agents have been found to have anti-apoptotic and anti-inflammatory mechanisms of action which may aid the resilience of retinal ganglion cells and enable them to withstand potential insults that trigger cell death. We highlight how these properties could be translated into clinical practice and the barriers needing to be overcome in order to achieve this.
The terms cosmeceutical and evidence-based may not belong in the same phrase. Cosmeceuticals are considered by many scientists to represent fluff without stuff, and indeed the reader may come to a similar conclusion at the end of this chapter. Nevertheless, it is worthwhile to examine the state of the science for cosmeceuticals as they represent an ever-expanding field in dermatology with perhaps much yet unrealized promise. Cosmeceuticals extend beyond cosmetics to enhance skin functioning, usually aiming to return the skin to a more youthful state. For example, wrinkle-reducing moisturizers, antioxidant serums, and skin-lightening salves all fall into this category. Cosmeceuticals are somewhat confusing, however, as both prescription and over-the-counter (OTC) products have been labeled by this term. Drug cosmeceuticals include topical retinoids for improving dermal collagen production, topical minoxidil for enhanced scalp hair growth, and eflornithine for facial hair growth reduction. These products will not be discussed, as they are not available to the consumer except by prescription. The second category of cosmeceuticals includes OTC drugs, such as sunscreens and antiperspirants. These also are outside the realm of this chapter. The discussion will focus on cosmeceuticals that are topically applied for the purpose of improving skin appearance.
Objectives
Migraine ranks among the most frequent neurological disorders globally. Co‐enzyme Q10 (CoQ10) is a nutritional agent that might play a preventative role in migraine. This meta‐analysis aimed to investigate the effects of CoQ10 as a supplemental agent in migraine.
Subjects and methods
Web of Science, PubMed and Cochrane Library were searched for potential articles that assessed the effects of CoQ10 on migraine. Data were extracted by two independent reviewers and analyzed with Revman 5.2 software.
Results
We included 5 studies with 346 patients (120 pediatric and 226 adult subjects) in the meta‐analysis. CoQ10 was comparable with placebo with respect to migraine attacks/month (P = 0.08) and migraine severity/day (P = 0.08). However, CoQ10 was more effective than placebo in reducing migraine days/month (P <0.00001) and migraine duration (P = 0.009).
Conclusion
This is the first study to demonstrate the effects of CoQ10 supplementation on migraine. The results support the use of CoQ10 as a potent therapeutic agent with respect to migraine duration and migraine days per month. Nonetheless, more studies are needed to support the conclusions.
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The elderly population is rapidly growing in almost all parts of the world, and with the increase in the numbers of elderly people, the specific nutrition-related problems of the elderly years take on greater significance in terms of healthcare and health resources. This chapter discusses the biological processes that are responsible for ageing and the degeneration of physiological systems that is associated with the elderly years. It considers the particular nutrient requirements that accompany this life stage and describes some of the main nutrition-related problems of the elderly. The elderly have similar nutrient requirements to younger adults, but declining energy expenditure means that the optimal diet should be more nutrient dense. The elderly population are the main at-risk group for malnutrition in developed countries. Osteoporosis, gastrointestinal diseases, and anaemia are prevalent in most elderly people.
Current consumer trends have brought the nutritional supplements, among other antiaging products, into a high-profit enterprise. The main pillar of the marketing campaign is the pharmacological activity of nutrients that are called “nutraceuticals.” Nutrition has long been associated with skin health, beauty, and aging. Although the frequency of nutritional deficiencies is low in the developed countries, incomplete diets could influence health and affect skin health. Oral supplementation with vitamins, trace minerals, and fatty acids has been shown in clinical studies to modulate skin function and possibly hair health. Vitamin, carotenoid, and fatty acid supplementation may prevent skin diseases. Vegetables, legumes, and olive oil may be protective against cutaneous actinic damage and skin wrinkling. Oral fish polysaccharide supplementation may improve dermal thickness, skin wrinkling, color, and viscoelasticity. Benefits on hydration, skin barrier, defense against inflammation, and skin roughness were reported under intake of essential fatty acids. Carotenoids (pro-vitamin A) as well as the vitamins C and E have been extensively associated with the protection of the skin against photodamage (sunburn, tanning) and subsequently photoaging, as well as precancerous conditions and cancers.
Myopathy is among the well documented and the most disturbing adverse effects of statins. The underlying mechanism is still unknown. Mitochondrial dysfunction related to coenzyme Q10 decline is one of the proposed theories. The present study aimed to investigate the mechanism of atorvastatin-induced myopathy in rats. In addition, the mechanism of the coenzyme Q10 protection was investigated with special focus of mitochondrial alterations. Sprague-Dawely rats were treated orally either with atorvastatin (100 mg/kg) or atorvastatin and coenzyme Q10 (100 mg/kg). Myopathy was assessed by measuring serum creatine kinase (CK) and myoglobin levels together with examination of necrosis in type IIB fiber muscles. Mitochondrial dysfunction was evaluated by measuring muscle lactate/pyruvate ratio, ATP level, pAkt as well as mitochondrial ultrastructure examination. Atorvastatin treatment resulted in a rise in both CK (2X) and myoglobin (6X) level with graded degrees of muscle necrosis. Biochemical determinations showed prominent increase in lactate/pyruvate ratio and a decline in both ATP (>80%) and pAkt (>50%) levels. Ultrastructure examination showed mitochondrial swelling with disrupted organelle membrane. Co-treatment with coenzyme Q10 induced reduction in muscle necrosis as well as in CK and myoglobin levels. In addition, coenzyme Q10 improved all mitochondrial dysfunction parameters including mitochondrial swelling and disruption. These results presented a model for atorvastatin-induced myopathy in rats and proved that mitochondrial dysfunction is the main contributor in statin-myopathy pathophysiology.
The knowledge of coenzyme Q levels in tissues, organs, and subcellular compartments is of outstanding interest. A wide amount of data regarding coenzyme Q distribution and occurrence was collected in the last decades; nevertheless the data are often hard to compare because of the different extraction methods and different analytical techniques used. We have undertaken a systematic study for detecting the ubiquinone content in subcellular compartments, cells, and whole-tissue homogenates by a previously standardized HPLC method performed after an extraction procedure identical for all samples. It was confirmed that the major coenzyme Q homologue in rat tissues is coenzyme Q9; however, it was pointed out that all the rodents samples tested contain more than one coenzyme Q homologue. The coenzyme Q homologue distribution is tissue dependent with relatively high coenzyme Q10 content in brain mitochondria, irrespective of the rat strain used. There is no constant relationship of the coenzyme Q content in mitochondria and microsomes fractions. Most organisms tested (including other mammals, bird and fish specimens) have only coenzyme Q10, while the protozoan Tetrahymena pyriformis contains only coenzyme Q8.
During the course of measuring superoxide dismutase (SOD) activity in rat breast tissue, interferences in the nitroblue tetrazolium (NBT) and cytochrome c assay systems were noted. These interferences inhibit accurate measurement of SOD activity in breast tissues, necessitating the development of a new NBT-based assay that includes compounds capable of inhibiting tissue specific interferences. The most effective compounds were metal chelators that were also electron transport chain inhibitors. Bathocuproine sulfonate (BCS) was the most effective of these compounds. The inclusion of BCS in the NBT assay system was shown to make the accurate measurement of SOD activity in tissues with interferences possible.
Rates of mitochondrial superoxide anion radical (O·̄2) generation are known to be inversely correlated with the maximum life span potential of different mammalian species. The
objective of this study was to understand the possible mechanism(s) underlying such variations in the rate of O·̄2 generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O·̄2 generation was tested. A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat,
sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity, indicated that the rate of O·̄2 generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ9 and inversely related to the amount of CoQ10, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O·̄2 generation, rat heart SMPs, naturally containing mainly CoQ9 and cow heart SMPs, with high natural CoQ10 content, were chosen for depletion/reconstitution experiments. Repeated extractions of rat heart SMPs with pentane exponentially
depleted both CoQ homologues while the corresponding rates of O·̄2 generation and oxygen consumption were lowered linearly. Reconstitution of both rat and cow heart SMPs with different amounts
of CoQ9 or CoQ10 caused an initial increase in the rates of O·̄2 generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were
no differences in the rates of O·̄2generation between SMPs reconstituted with CoQ9 or CoQ10. Only at concentrations that were considerably higher than the physiological level, the SMPs reconstituted with CoQ9 exhibited higher rates of O·̄2 generation than those obtained with CoQ10. These in vitrofindings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations
in the rates of mitochondrial O·̄2 generation in different mammalian species.
Our objective was to assess effects of dietary supplementation with coenzyme Q10 (CoQ) on blood pressure and glycaemic control in subjects with type 2 diabetes, and to consider oxidative stress as a potential mechanism for any effects.
Seventy-four subjects with uncomplicated type 2 diabetes and dyslipidaemia were involved in a randomised double blind placebo-controlled 2x2 factorial intervention.
The study was performed at the University of Western Australia, Department of Medicine at Royal Perth Hospital, Australia.
Subjects were randomly assigned to receive an oral dose of 100 mg CoQ twice daily (200 mg/day), 200 mg fenofibrate each morning, both or neither for 12 weeks.
We report an analysis and discussion of the effects of CoQ on blood pressure, on long-term glycaemic control measured by glycated haemoglobin (HbA(1c)), and on oxidative stress assessed by measurement of plasma F2-isoprostanes.
Fenofibrate did not alter blood pressure, HbA(1c), or plasma F2-isoprostanes. There was a 3-fold increase in plasma CoQ concentration (3.4+/-0.3 micro mol/l, P<0.001) as a result of CoQ supplementation. The main effect of CoQ was to significantly decrease systolic (-6.1+/-2.6 mmHg, P=0.021) and diastolic (-2.9+/-1.4 mmHg, P=0.048) blood pressure and HbA(1c) (-0.37+/-0.17%, P=0.032). Plasma F2-isoprostane concentrations were not altered by CoQ (0.14+/-0.15 nmol/l, P=0.345).
These results show that CoQ supplementation may improve blood pressure and long-term glycaemic control in subjects with type 2 diabetes, but these improvements were not associated with reduced oxidative stress, as assessed by F2-isoprostanes.
This study was supported by a grant from the NH&MRC, Australia.
To explore the role of mitochondrial activity in the aging process, we have lowered the activity of the electron transport
chain and adenosine 5′-triphosphate (ATP) synthase with RNA interference (RNAi) in Caenorhabditis elegans. These perturbations reduced body size and behavioral rates and extended adult life-span. Restoring messenger RNA to near-normal
levels during adulthood did not elevate ATP levels and did not correct any of these phenotypes. Conversely, inhibiting respiratory-chain
components during adulthood only did not reset behavioral rates and did not affect life-span. Thus, the developing animal
appears to contain a regulatory system that monitors mitochondrial activity early in life and, in response, establishes rates
of respiration, behavior, and aging that persist during adulthood.
This chapter examines the stability and preparation of catalase. Catalase combines rapidly with H2O2 or alkyl hydroperoxides. The rate constant for the reaction catalase + H2O2 is of the order of 10⁷ s⁻¹ X mole⁻¹. With the alkyl hydroperoxides, the constant decreases with increasing chain length. In comparison to the formation of the primary compound the back reaction can be disregarded. The turnover number for the decomposition of hydrogen peroxide is 2.5 × 10⁶ to 5 × 10⁶ moles/min. The maximum rise in temperature after the start of the reaction can serve as an approximate measure of the activity. The manometric method is considerably more accurate than the volumetric measurement of oxygen with the Katalaser. The paper disk method is rapid and easy to carry out but is not so accurate. In this method the enzyme activity is measured by the rate at which a filter paper disk soaked in the sample solution is carried to the surface of a H2O2 solution by the oxygen liberated. The temperature coefficient for the decomposition of H2O2 is about 5% per degree between 0 and + 10°C.
Mutations in the C. elegans maternal-effect gene clk-1 are highly pleiotropic, affecting the duration of diverse developmental and behavioral processes. They result in an average slowing of embryonic and post-embryonic development, adult rhythmic behaviors, reproduction, and aging.(1) CLK-1 is a highly conserved mitochondrial protein,(2,3) but even severe clk-1 mutations affect mitochondrial respiration only slightly.(3) Here, we review the evidence supporting the regulatory role of clk-1 in physiological timing. We also discuss possible models for the action of CLK-1, in particular, one proposing that CLK-1 is involved in the coordination of mitochondrial and nuclear function. BioEssays 22:48–56, 2000. ©2000 John Wiley & Sons, Inc.
The objective of this study was to examine the possible involvement of oxygen free radicals in the aging process. Rates of mitochondrial O2.− and H2O2 production and oxygen consumption in the kidney and the heart were compared among seven different mammalian species namely, mouse, hamster, rat, guinea pig, rabbit, pig, and cow, whose maximum life span potential (MLSP) varies from 3.5 to 30 years. The rates of mitochondrial O2.− and H2O2 generation were inversely correlated to MLSP, and directly related to specific metabolic rate and state 4 mitochondrial respiration. Results of this study indicate that under identical conditions, mitochondria from shoter-lived species produce relatively higher amounts of reactive oxygen species than those from the longer-lived species, and, thus, support the free radical hypothesis of aging.
Antimycin-inhibited bovine heart submitochondrial particles generate O2- and H2O2 with succinate as electron donor. H2O2 generation involves the action of the mitochondrial superoxide dismutase, in accordance with the McCord & Fridovich [(1969) j. biol. Chem. 244, 6049-6055] reaction mechanism. Removal of ubiquinone by acetone treatment decreases the ability of mitochondrial preparations to generate O2- and H2O2, whereas supplementation of the depleted membranes with ubiquinone enhances the peroxide-generating activity in the reconstituted membranes. Addition of superoxide dismutase to ubiquinone-reconstituted membranes is essential in order to obtain maximal rates of H2O2 generation since the acetone treatment of the membranes apparently inactivates (or removes) the mitochondrial superoxide dismutase. Parallel measurements of H2O2 production, succinate dehydrogenase and succinate-cytochrome c reductase activities show that peroxide generation by ubiquinone-supplemented membranes is a monotonous function of the reducible ubiquinone content, whereas the other two measured activities reach saturation at relatively low concentrations of reducible quinone. Alkaline treatment of submitochondrial particles causes a significant decrease in succinate dehydrogenase activity and succinate-dependent H2O2 production, which contrasts with the increase of peroxide production by the same particles with NADH as electron donor. Solubilized succinate dehydrogenase generates H2O2 at a much lower rate than the parent submitochondrial particles. It is postulated that ubisemiquinone (and ubiquinol) are chiefly responsible for the succinate-dependent peroxide production by the mitochondrial inner membrane.
Publisher Summary This chapter discusses methods to determine carbonyl content in oxidatively modified proteins. The methods described are (1) reduction of the carbonyl group to an alcohol with tritiated borohydride; (2) reaction of the carbonyl group with 2,4-dinitrophenylhydrazine to form the 2,4-dinitrophenylhydrazone; (3) reaction of the carbonyl with fluorescein thiosemicarbazide to form the thiosemicarbazone; and (4) reaction of the carbonyl group with fluorescein amine to form a Schiff base followed by reduction to the secondary amine with cyanoborohydride. Van Poelje and Snell have also quantitated protein-bound pyruvoyl groups through formation of a Schiff base with p-aminobenzoic acid followed by reduction with cyanoborohydride. Although a systematic investigation has not appeared, this method should also be useful in detecting other protein-bound carbonyl groups. Carbonyl content of proteins is expressed as moles carbonyl/mole subunit for purified proteins of known molecular weight. For extracts, the results may be given as nanomoles carbonyl/milligram protein. For a protein having a molecular weight of 50,000, a carbonyl content of 1 mol carbonyl/mol protein corresponds to 20 nmol carbonyl/mg proteins.
Ubiquinones and tocopherols (vitamin E) are intrinsic lipid components which have a stabilizing function in many membranes attributed to their antioxidant activity. The antioxidant effects of tocopherols are due to direct radical scavenging. Although ubiquinones also exert antioxidant properties the specific molecular mechanisms of their antioxidant activity may be due to: (i) direct reaction with lipid radicals or (ii) interaction with chromanoxyl radicals resulting in regeneration of vitamin E. Lipid peroxidation results have now shown that tocopherols are much stronger membrane antioxidants than naturally occurring ubiquinols (ubiquinones). Thus direct radical scavenging effects of ubiquinols (ubiquinones) might be negligible in the presence of comparable or higher concentrations of tocopherols. In support of this our ESR findings show that ubiquinones synergistically enhance enzymic NADH- and NADPH-dependent recycling of tocopherols by electron transport in mitochondria and microsomes. If ubiquinols were direct radical scavengers their consumption would be expected. Further proving our conclusion HPLC measurements demonstrated that ubiquinone-dependent sparing of tocopherols was not accompanied by ubiquinone consumption.
Much evidence indicates that superoxide is generated from O2 in a cyanide-sensitive reaction involving a reduced component of complex III of the mitochondrial respiratory chain, particularly when antimycin A is present. Although it is generally believed that ubisemiquinone is the electron donor to O2, little experimental evidence supporting this view has been reported. Experiments with succinate as electron donor in the presence of antimycin A in intact rat heart mitochondria, which contain much superoxide dismutase but little catalase, showed that myxothiazol, which inhibits reduction of the Rieske iron-sulfur center, prevented formation of hydrogen peroxide, determined spectrophotometrically as the H2O2-peroxidase complex. Similarly, depletion of the mitochondria of their cytochrome c also inhibited formation of H2O2, which was restored by addition of cytochrome c. These observations indicate that factors preventing the formation of ubisemiquinone also prevent H2O2 formation. They also exclude ubiquinol, which remains reduced under these conditions, as the reductant of O2. Since cytochrome b also remains fully reduced when myxothiazol is added to succinate- and antimycin A-supplemented mitochondria, reduced cytochrome b may also be excluded as the reductant of O2. These observations, which are consistent with the Q-cycle reactions, by exclusion of other possibilities leave ubisemiquinone as the only reduced electron carrier in complex III capable of reducing O2 to O2-.
1. Pigeon heart mitochondria produce H(2)O(2) at a maximal rate of about 20nmol/min per mg of protein. 2. Succinate-glutamate and malate-glutamate are substrates which are able to support maximal H(2)O(2) production rates. With malate-glutamate, H(2)O(2) formation is sensitive to rotenone. Endogenous substrate, octanoate, stearoyl-CoA and palmitoyl-carnitine are by far less efficient substrates. 3. Antimycin A exerts a very pronounced effect in enhancing H(2)O(2) production in pigeon heart mitochondria; 0.26nmol of antimycin A/mg of protein and the addition of an uncoupler are required for maximal H(2)O(2) formation. 4. In the presence of endogenous substrate and of antimycin A, ATP decreases and uncoupler restores the rates of H(2)O(2) formation. 5. Reincorporation of ubiquinone-10 and ubiquinone-3 to ubiquinone-depleted pigeon heart mitochondria gives a system in which H(2)O(2) production is linearly related to the incorporated ubiquinone. 6. The generation of H(2)O(2) by pigeon heart mitochondria in the presence of succinate-glutamate and in metabolic state 4 has an optimum pH value of 7.5. In states 1 and 3u, and in the presence of antimycin A and uncoupler, the optimum pH value is shifted towards more alkaline values. 7. With increase of the partial pressure of O(2) to the hyperbaric region the formation of H(2)O(2) is markedly increased in pigeon heart mitochondria and in rat liver mitochondria. With rat liver mitochondria and succinate as substrate in state 4, an increase in the pO(2) up to 1.97MPa (19.5atm) increases H(2)O(2) formation 10-15-fold. Similar pO(2) profiles were observed when rat liver mitochondria were supplemented either with antimycin A or with antimycin A and uncoupler. No saturation of the system with O(2) was observed up to 1.97MPa (19.5atm). By increasing the pO(2) to 1.97MPa (19.5atm), H(2)O(2) formation in pigeon heart mitochondria with succinate as substrate increased fourfold in metabolic state 4, with antimycin A added the increase was threefold and with antimycin A and uncoupler it was 2.5-fold. In the last two saturation of the system with oxygen was observed, with an apparent K(m) of about 71kPa (0.7-0.8atm) and a V(max.) of 12 and 20nmol of H(2)O(2)/min per mg of protein. 8. It is postulated that in addition to the well-known flavin reaction, formation of H(2)O(2) may be due to interaction with an energy-dependent component of the respiratory chain at the cytochrome b level.
Quantitative analyses of individual ubiquinones (Q) homologs in biological samples have been performed by high-performance liquid chromatography (HPLC) combined with an ultraviolet spectrometric detector (UVD) or by mass spectrometry (MS). An electrochemical detector (ECD) for HPLC was confirmed to be simple and sensitive for the determination of Q. However, only Q was determined by these methods. For the determination of QH2 (ubiquinol) and Q in mitochondria, submitochondrial particle and cell-free bacterial homogenates, the dual-wavelength spectrometric method has been generally used. The method, however, cannot simultaneously measure the amounts of QH2 and Q in whole tissues owing to the presence of vitamin A and other interfering compounds, which have an absorbance in the same spectral region as Q and undergo an absorption change by chemical reduction. The dual-wavelength spectrometric method cannot separately determine individual Q homologs. The analytical procedure described was developed to provide a rapid, sensitive, and direct assay method for QH2 and Q in biological samples. This method is based on extraction from tissues, mitochondria, microsomal fractions, or plasma with organic solvents, followed by quantitation by means of reversed-phase chromatography with UVD and ECD.
A method of high performance liquid chromatography with both of a UV detector and an electrochemical detector for the simultaneous determination of ubiquinone and ubiquinol was established. This method could sensitively and specifically measure the redox state of ubiquinone in mitochondria and tissues.
This presentation is a brief review of current knowledge concerning some biochemical, physiological and medical aspects of the function of ubiquinone (coenzyme Q) in mammalian organisms. In addition to its well-established function as a component of the mitochondrial respiratory chain, ubiquinone has in recent years acquired increasing attention with regard to its function in the reduced form (ubiquinol) as an antioxidant. Ubiquinone, partly in the reduced form, occurs in all cellular membranes as well as in blood serum and in serum lipoproteins. Ubiquinol efficiently protects membrane phospholipids and serum low-density lipoprotein from lipid peroxidation, and, as recent data indicate, also mitochondrial membrane proteins and DNA from free-radical induced oxidative damage. These effects of ubiquinol are independent of those of exogenous antioxidants, such as vitamin E, although ubiquinol can also potentiate the effect of vitamin E by regenerating it from its oxidized form. Tissue ubiquinone levels are regulated through the mevalonate pathway, increasing upon various forms of oxidative stress, and decreasing during aging. Drugs inhibiting cholesterol biosynthesis via the mevalonate pathway may inhibit or stimulate ubiquinone biosynthesis, depending on their site of action. Administration of ubiquinone as a dietary supplement seems to lead primarily to increased serum levels, which may account for most of the reported beneficial effects of ubiquinone intake in various instances of experimental and clinical medicine.
Coenzyme Q is an important mitochondrial redox component and the only endogenously produced lipid-soluble antioxidant. Its tissue concentration decreases with aging and in a number of diseases; dietary supplementation of this lipid would fulfill important functions by counteracting coenzyme Q depletion. To investigate possible uptake, rats were administered 12 mumol coenzyme Q10/100 g body wt once daily by gastric intubation. The appearance of coenzyme Q10 in various tissues and blood after 6 h, 4 d or 8 d was studied. The control group of rats received rapeseed-soybean oil (the vehicle in the experimental group). Lipids were extracted with petroleum ethermethanol, and the reduced and oxidized forms of coenzyme Q9 and Q10 were separated and quantified by reversed-phase HPLC. In the plasma, the total coenzyme Q concentration was doubled after 4 d of treatment. Coenzyme Q10 was also recovered in liver homogenates, where, as in the plasma, it was largely in the reduced form. Uptake into the spleen could be to a large extent accounted for by the blood content of this organ. No dietary coenzyme Q10 was recovered in the heart or kidney. The uptake in the whole body was 2-3% of the total dose. Coenzyme Q10 found in the liver was located mainly in the lysosomes. Dietary coenzyme Q10 did not influence the endogenous biosynthesis of coenzyme Q9. This is in contrast to dietary cholesterol, which down-regulates cholesterol biosynthesis. The dietary coenzyme Q10 level in the plasma decreased to approximately 50% after 4 d. These results suggest that dietary coenzyme Q10 may play a role primarily in the blood and that no appreciable uptake occurs into tissues.
This article is a study of the relationship between lipid peroxidation and protein modification in beef heart submitochondrial particles, and the protective effect of endogenous ubiquinol (reduced coenzyme Q) against these effects. ADP-Fe3+ and ascorbate were used to initiate lipid peroxidation and protein modification, which were monitored by measuring TBARS and protein carbonylation, respectively. Endogenous ubiquinone was reduced by the addition of succinate and antimycin. The parameters investigated included extraction and reincorporation of ubiquinone, and comparison of the effect of ubiquinol with those of various antioxidant compounds and enzymes, as well as the iron chelator EDTA. Under all conditions employed there was a close correlation between lipid peroxidation and protein carbonylation, and the inhibition of these effects by endogenous ubiquinol. SDS-PAGE analysis revealed a differential effect on individual protein components and its prevention by ubiquinol. Conceivable mechanisms behind the observed oxidative modifications of membrane phospholipids and proteins and of the role of ubiquinol in preventing these effects are considered.
The dietary uptake of alpha-tocopherol and coenzyme Q was investigated in rats. Rats were fed diets supplemented with alpha-tocopherol or coenzyme Q10 (1 g/kg diet) or an unsupplemented control diet. In control rat tissues, the content of coenzyme Q was 4-11 times higher than that of alpha-tocopherol, but in plasma, the ratio was reversed. Among the subcellular fractions of rat liver homogenate, Golgi vesicles and lysosomes had the highest alpha-tocopherol concentration, and high concentrations of coenzyme Q were observed in the outer and inner mitochondrial membranes as well as in lysosomes, Golgi vesicles and plasma membranes. The uptake of alpha-tocopherol into the liver and plasma reached a maximal level after only 2 d of supplementation, whereas in the kidney, heart, muscle and brain, the levels continued to increase throughout the 6-wk treatment period. In contrast, dietary coenzyme Q was taken up into the liver and plasma only, and not into the other organs. This lipid appeared mainly in the Golgi system, whereas alpha-tocopherol exhibited a more general cellular distribution. The decay of the supplied alpha-tocopherol was slow in the various organs, but the disappearance of coenzyme Q was rapid from both liver and plasma. Pretreatment of rats with alpha-tocopherol increased the levels of both endogenous and exogenous coenzyme Q in the liver and plasma. These results demonstrate that the uptake of alpha-tocopherol from the diet is an extensive and general phenomenon at both the tissue and cellular levels, in contrast to the selective and restricted uptake of coenzyme Q.
The effect of lifelong oral supplementation with ubiquinone Q10 (10 mg/kg/day) was examined in Sprague-Dawley rats and C57/B17 mice. There were no significant differences in survival or life-span found in either rats or mice. Histopathologic examination of different rat tissues showed no differences between the groups. In Q10 supplemented rats, plasma and liver Q10 levels were 2.6 to 8.4 times higher at all age points than in control rats. Interestingly, in supplemented rats the Q9 levels also were significantly higher (p<0.05) in plasma and liver at ages 18 and 24 months. Neither Q9 nor Q10 levels were affected by supplementation in kidney, heart, or brain tissues. In spite of the significant changes in plasma and liver ubiquinone concentrations, lifelong Q10 supplementation did not prolong or shorten the lifespan of either rats or mice.
The objective of this study was to elucidate the anti-oxidative roles of coenzyme Q (CoQ) and alpha-tocopherol in mitochondrial membranes by determining whether CoQ directly scavenges peroxyl- and alkoxyl-radicals or indirectly regenerates alpha-tocopherol during autooxidation of mitochondrial membranes. A comparison of the interaction between alpha-tocopherol and CoQ during autooxidation was made between bovine and rat heart mitochondria, which differ approximately 15-fold in their alpha-tocopherol content. Autooxidation of both bovine and rat heart mitochondria resulted in the formation of thiobarbituric-acid-reactive substances and protein carbonyls; however, the differences in the autooxidizability of mitochondria between rat and bovine heart mitochondrial membranes were relatively minor. Supplementation of rat heart mitochondria with succinate caused reduction of CoQ to ubiquinol while alpha-tocopherol concentration remained unaffected during autooxidation. In contrast, in the absence of succinate, CoQ was present in the oxidized form (ubiquinone) and the mitochondrial membranes were depleted of alpha-tocopherol. CoQ concentrations remained unchanged over time irrespective of the presence or absence of succinate. In the absence of succinate, autooxidation of bovine SMPs, supplemented with different amounts of alpha-tocopherol, was inversely related to the amount of alpha-tocopherol, whereas in the presence of succinate autooxidation was greatly reduced. Results of this study indicate that during autooxidation of mitochondria, alpha-tocopherol acts as the direct radical scavenger, whereas ubiquinol regenerates alpha-tocopherol.
Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.
In elderly patients the results of cardiac interventions are inferior to those in the young. A possible contributing factor is an age-related reduction in cellular energy transduction during the intervention which may induce aerobic or ischemic stress. To investigate whether coenzyme Q10 (CoQ10) improves the response to aerobic stress, functional recoveries of senescent and young rat hearts after rapid pacing were compared with or without CoQ10.
Young (4.8 +/- 0.1 months) and senescent (35.3 +/- 0.2 months) rats were given daily intraperitoneal injections of CoQ10 (4 mg/kg) or vehicle for 6 weeks. Their isolated hearts were rapidly paced at 510 beats per minute for 120 min to induce aerobic stress without ischemia.
In senescent hearts pre-pacing cardiac work was 74% and oxygen consumption (MVO2) 66% of that in young hearts. CoQ10 treatment abolished these differences. After pacing, the untreated senescent hearts, compared to young, showed reduced recovery of pre-pacing work, (16.8 +/- 4.3 vs. 44.5 +/- 7.4%; P < 0.01). CoQ10 treatment in senescent hearts improved recovery of work, (48.1 +/- 4.1 vs. 16.8 +/- 4.3%; P < 0.0001) and MVO2 (82.1 +/- 2.8 vs. 61.3 +/- 4.0%; P < 0.01) in treated versus untreated hearts respectively. Post-pacing levels of these parameters in CoQ10 treated senescent hearts were as high as in young hearts.
(1) Senescent rat hearts have reduced baseline function and reduced tolerance to aerobic stress compared to young hearts. (2) Pre-treatment with CoQ10 improves baseline function of the senescent myocardium and its tolerance to aerobic stress.
The objective of this study was to elucidate the mechanisms that govern the variations in the rates of mitochondrial superoxide anion radical (O2-*) generation in different species. The amounts of coenzyme Q (CoQ) associated with mitochondrial membrane proteins were compared in five different mammalian species, namely mouse, rat, rabbit, pig, and cow. Micelles of cardiac mitochondria were prepared using Triton X-100 or deoxycholate (DOC) as detergents, and the micelles containing mitochondrial proteins were sedimented by sucrose density ultracentrifugation. The amount of CoQ present in both types of micelles varied in different species, whereas alpha-tocopherol, another lipoidal molecule in mitochondrial membranes, could not be detected in the micelles of any of these species. The amounts of CoQ bound to mitochondrial proteins in DOC micelles were higher in those mammalian species where CoQ10 was the predominant CoQ homologue, and the amounts were found to be inversely correlated with the rate of mitochondrial 02-* generation among different species. Results also indicated that mitochondrial CoQ exists in at least two distinct pools, one of which is associated with the membrane proteins. The degree of association between CoQ and membrane proteins appears to be a factor determining the rate of mitochondrial O2-* generation.
The purpose of the present study was to examine the role of mitochondria in the aging process by determining whether the activities of various electron transport chain oxidoreductases are deleteriously affected during aging and whether the hypothesized age-related alterations in different tissues follow a common pattern. Activities of respiratory complexes I, II, III, and IV were measured in mitochondria isolated from brain, heart, skeletal muscle, liver, and kidney of young (3.5 months), adult (12-14 months), and old (28-30 months) C57BL/6 mice. Activities of some individual complexes were decreased in old animals, but no common pattern can be discerned among various tissues. In general, activities of the complexes were more adversely affected in tissues such as brain, heart, and skeletal muscle, whose parenchyma is composed of postmitotic cells, than those in the liver and kidney, which are composed of slowly dividing cells. The main feature of age-related potentially dysfunctional alterations in tissues was the development of a shift in activity ratios among different complexes, such that it would tend to hinder the ability of mitochondria to effectively transfer electrons down the respiratory chain and thus adversely affect oxidative phosphorylation and/or autooxidizability of the respiratory components.
The isoprenylated benzoquinone coenzyme Q is a redox-active lipid essential for electron transport in aerobic respiration. Here, we show that withdrawal of coenzyme Q (Q) from the diet of wild-type nematodes extends adult life-span by approximately 60%. The longevity of clk-1, daf-2, daf-12, and daf-16 mutants is also extended by a Q-less diet. These results establish the importance of Q in life-span determination. The findings suggest that Q and the daf-2 pathway intersect at the mitochondria and imply that a concerted production coupled with enhanced scavenging of reactive oxygen species contributes to the substantial life-span extension.
Coenzyme Q (CoQ(10)) is a component of the mitochondrial electron transport chain and also a constituent of various cellular membranes. It acts as an important in vivo antioxidant, but is also a primary source of O(2)(-*)/H(2)O(2) generation in cells. CoQ has been widely advocated to be a beneficial dietary adjuvant. However, it remains controversial whether oral administration of CoQ can significantly enhance its tissue levels and/or can modulate the level of oxidative stress in vivo. The objective of this study was to determine the effect of dietary CoQ supplementation on its content in various tissues and their mitochondria, and the resultant effect on the in vivo level of oxidative stress. Rats were administered CoQ(10) (150 mg/kg/d) in their diets for 4 and 13 weeks; thereafter, the amounts of CoQ(10) and CoQ(9) were determined by HPLC in the plasma, homogenates of the liver, kidney, heart, skeletal muscle, brain, and mitochondria of these tissues. Administration of CoQ(10) increased plasma and mitochondria levels of CoQ(10) as well as its predominant homologue CoQ(9). Generally, the magnitude of the increases was greater after 13 weeks than 4 weeks. The level of antioxidative defense enzymes in liver and skeletal muscle homogenates and the rate of hydrogen peroxide generation in heart, brain, and skeletal muscle mitochondria were not affected by CoQ supplementation. However, a reductive shift in plasma aminothiol status and a decrease in skeletal muscle mitochondrial protein carbonyls were apparent after 13 weeks of supplementation. Thus, CoQ supplementation resulted in an elevation of CoQ homologues in tissues and their mitochondria, a selective decrease in protein oxidative damage, and an increase in antioxidative potential in the rat.
The main purpose of this article is to provide a critical overview of the currently available evidence bearing on the validity of the oxidative stress hypothesis of aging, which postulates that senescence-associated attenuations in physiological functions are caused by molecular oxidative damage. Several lines of correlative evidence support the predictions of the hypothesis, e.g., macromolecular oxidative damage increases with age and tends to be associated with life expectancy of organisms. Nevertheless, a direct link between oxidative stress and aging has not as yet been established. Single gene mutations have been reported to extend the life spans of lower organisms, such as nematodes and insects; however, such prolongations of chronological clock time survival are usually associated with decreases in the rate of metabolism and reproductive output without affecting the metabolic potential, i.e., the total amount of energy consumed during life. Studies on genetic manipulations of the aging process have often been conducted on relatively short-lived strains that are physiologically weak, whereby life-span extensions can not be unambiguously assigned to a slowing effect on the rate of aging. It is concluded that although there is considerable evidence implicating oxidative stress in the aging process, additional evidence is needed to clearly define the nature of the involvement.
Radioactive coenzyme Q(10) ([(3)H]CoQ) was synthesized in a way that the metabolites produced retained the radioactivity. Administration of the lipid to rats intraperitoneally resulted in an efficient uptake into the circulation, with high concentrations found in spleen, liver, and white blood cells; lower concentrations in adrenals, ovaries, thymus, and heart; and practically no uptake in kidney, muscle, and brain. In liver homogenate most [(3)H]CoQ appeared in the organelles, but it was also present in the cytosol and transport vesicles. Mitochondria, purified on a metrizamide gradient, had a very low concentration of [(3)H]CoQ, which was mainly present in the lysosomes. All organs that took up the labeled lipid also contained water-soluble metabolites. The majority of metabolites excreted through the kidney and appeared in the urine. Some metabolites were also present in the feces, which further contained nonmetabolized [(3)H]CoQ, excreted through the bile. The major metabolites were purified from the urine, and the mass spectrometric fragmentation showed that these compounds, containing the ring with a short side chain, are phosphorylated. Thus, the results demonstrate that CoQ is metabolized in all tissues, the metabolites are phosphorylated in the cells, transported in the blood to the kidney, and excreted into the urine.
Ubiquinone (coenzyme Q; Q) is a key factor in the mitochondria electron transport chain, but it also functions as an antioxidant and as a cofactor of mitochondrial uncoupling proteins. Furthermore, Q isoforms balance in Caenorhabditis elegans is determined by both dietary intake and endogenous biosynthesis. In the absence of synthesis, withdrawal of dietary Q8 in adulthood extends life span. Thus, Q plays an important role in the aging process and understanding its synthesis acquires a new impetus. We have identified by RNA interference (RNAi) eight genes, including clk-1, involved in ubiquinone biosynthesis in C. elegans feeding animals with dsRNA-containing Escherichia coli HT115 strains. Silenced C. elegans showed lower levels of both endogenous Q9 and Q8 provided by diet, produced less superoxide without a significant modification of mitochondrial electron chain, and extended life span compared with non-interfered animals. E. coli strains harboring dsRNA also interfered with their own Q8 biosynthesis. These findings suggest that more efficient electron transport between a lower amount of Q and electron transport capacity of the mitochondrial complexes leads to less production of reactive oxygen species that contributes to extension of life span in the nematode C. elegans.
Arteriopathy is the principal complication of type 2 diabetes mellitus. It develops from endothelial dysfunction, which we have hypothesised occurs in diabetes primarily as a consequence of dyslipidaemia and oxidative stress. Fenofibrate and CoQ may improve endothelial function by regulating dyslipidaemia and oxidative stress, respectively. We therefore aimed to assess the independent and combined effects of fenofibrate and coenzyme Q(10) (CoQ) on endothelium-dependent and endothelium-independent vasodilator function of the forearm microcirculation in type 2 diabetes. Eighty dyslipidaemic type 2 diabetics were randomized to receive fenofibrate (200 mg/daily), CoQ (200 mg/daily), fenofibrate plus CoQ (200+200 mg daily), or placebo for 12 weeks. Forearm microcirculatory function was assessed with venous occlusion plethysmography during the infusion of acetylcholine (ACh), bradykinin (BK), sodium nitroprusside (SNP) and N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery. Blood flow responses were calculated as area under the curve (AUC). Fenofibrate significantly lowered plasma cholesterol, triglyceride and fibrinogen (P<0.001), and elevated HDL-cholesterol and homocysteine (P<0.001). CoQ did not change plasma isoprostanes, but significantly lowered systolic blood pressure and HbA(1c) (P<0.05). Fenofibrate plus CoQ significantly improved (P<0.05) the AUC for ACh, BK and SNP without significantly altering basal responses to L-NMMA. Fenofibrate or CoQ alone did not significantly alter blood flow responses. Improvements in blood flow were independent of changes in plasma lipids, blood pressure, homocysteine and isoprostanes, but were correlated (P=0.013) with HbA(1c). In conclusion, in this factorial trial we found that only the combination of fenofibrate and CoQ markedly improved endothelial and non-endothelial forearm vasodilator function in dyslipidemic type 2 diabetic patients. The favourable vascular effect of this therapeutic combination could be due to increase in the bioactivity of and/or responses to endothelium-derived relaxing factors, including nitric oxide, and this may entail synergistic stimulation of peroxisome proliferator-activated receptors.
The main purpose of this study was to determine whether the aging process in the mouse is associated with a pro-oxidizing shift in the redox state of glutathione and whether restriction of caloric intake, which results in the extension of life span, retards such a shift. Amounts of reduced and oxidized forms of glutathione (GSH and GSSG, respectively) and protein-glutathione mixed disulfides (protein-SSG) were measured in homogenates and mitochondria of liver, kidney, heart, brain, eye, and testis of 4, 10, 22, and 26 month old ad libitum-fed (AL) mice and 22 month old mice fed a diet containing 40% fewer calories than the AL group from the age of 4 months. The concentrations of GSH, GSSG, and protein-SSG vary greatly (approximately 10-, 30-, and 9-fold, respectively) from one tissue to another. During aging, the ratios of GSH:GSSG in mitochondria and tissue homogenates decreased, primarily due to elevations in GSSG content, while the protein-SSG content increased significantly. Glutathione redox potential in mitochondria became less negative, i.e., more pro-oxidizing, as the animal aged. Caloric restriction (CR) lowered the GSSG and protein-SSG content. Results suggest that the aging process in the mouse is associated with a gradual pro-oxidizing shift in the glutathione redox state and that CR attenuates this shift.