Article

Cofactor treatment improves ATP synthetic capacity in patients with oxidative stress

Article

Cofactor treatment improves ATP synthetic capacity in patients with oxidative stress

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Abstract

Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q(10) (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ(10) incubation was demonstrated, which supports the proposal that CoQ(10) may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

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... Decrease in CoQ10 level is commonly observed in individuals in late 30th and appears to co-occur with the age-related decline in fertility and increased rate of embryo aneuploidy, suggesting a contribution of the reduced expression of CoQ10 to ovarian ageing [20]. Several animal studies have demonstrated that CoQ10 protects ovarian reserve, counteracts physiological ovarian ageing by restoring mitochondrial function and increases the rate of embryo cleavage and blastocyst formation [21][22][23]. In the clinical setting, CoQ10 supplementation led to better response to ovulation induction and decreased odds of fetal aneuploidy in 35-43-year-old women [24,25]. ...
... ROS-induced DNA damage in ovary leads to genomic instability, mutations and apoptosis of oocytes, and is thought to be ameliorated by an antioxidant activity of CoQ10 [22]. CoQ10 has been also shown to improve mitochondrial function and restore energy production by mitochondria [23]. Mitochondrial dysfunction in oocytes results in decreased oxidative phosphorylation and suboptimal levels of mitochondria-generated ATP, which has been strongly associated with poor reproductive performance, including diminished ovarian reserve, poor oocyte quality, abnormal fertilization and deranged preimplantation embryo development [29,30]. ...
Article
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Background: Management of women with reduced ovarian reserve or poor ovarian response (POR) to stimulation is one of the major challenges in reproductive medicine. The primary causes of POR remain elusive and oxidative stress was proposed as one of the important contributors. It has been suggested that focus on the specific subpopulations within heterogeneous group of poor responders could assist in evaluating optimal management strategies for these patients. This study investigated the effect of anti-oxidant treatment with coenzyme Q10 (CoQ10) on ovarian response and embryo quality in young low-prognosis patients with POR. Methods: This prospective, randomized controlled study included 186 consecutive patients with POR stratified according to the POSEIDON classification group 3 (age < 35, poor ovarian reserve parameters). The participants were randomized to the CoQ10 pre-treatment for 60 days preceding IVF-ICSI cycle or no pre-treatment. The number of high quality embryos was a primary outcome measure. Results: A total of 169 participants were evaluated (76 treated with CoQ10 and 93 controls); 17 women were excluded due to low compliance with CoQ10 administration. The baseline demographic and clinical characteristics were comparable between the groups. CoQ10 pretreatment resulted in significantly lower gonadotrophin requirements and higher peak E2 levels. Women in CoQ10 group had increased number of retrieved oocytes (4, IQR 2-5), higher fertilization rate (67.49%) and more high-quality embryos (1, IQR 0-2); p < 0.05. Significantly less women treated with CoQ10 had cancelled embryo transfer because of poor embryo development than controls (8.33% vs. 22.89%, p = 0.04) and more women from treatment group had available cryopreserved embryos (18.42% vs. 4.3%, p = 0.012). The clinical pregnancy and live birth rates per embryo transfer and per one complete stimulation cycle tended to be higher in CoQ10 group but did not achieve statistical significance. Conclusion: Pretreatment with CoQ10 improves ovarian response to stimulation and embryological parameters in young women with poor ovarian reserve in IVF-ICSI cycles. Further work is required to determine whether there is an effect on clinical treatment endpoints.
... Moreover, CoQ10 treatment significantly increases the ATP synthetic capacity in cultured lymphocytes of patients and controls in vitro (Marriage et al., 2004). This suggests that CoQ10 may have a beneficial effect in the treatment of oxidative phosphorylation disorders (Haas, 2007;Marriage et al., 2004). ...
... Moreover, CoQ10 treatment significantly increases the ATP synthetic capacity in cultured lymphocytes of patients and controls in vitro (Marriage et al., 2004). This suggests that CoQ10 may have a beneficial effect in the treatment of oxidative phosphorylation disorders (Haas, 2007;Marriage et al., 2004). A study by Somayajulu et al. (2005) suggested that CoQ10 stabilizes the mitochondrial membrane when neuronal cells are subjected to oxidative stress because a pretreatment with CoQ10 maintained the mitochondrial membrane potential during oxidative stress and reduced the amount of mitochondrial ROS generated. ...
Article
Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD.
... Подавле- ние активности свободнорадикальных процессов в организме, коррекция липидного спектра плазмы и восстановление функциональной активности эн- дотелия сосудов на сегодняшний день являются ос- новополагающими факторами первичной и вторич- ной профилактики атеросклероза и ИБС. В связи с этим понятен интерес, который вызывает использо- вание в клинической практике убихинона -коэн- зима Q 10 (КоQ 10 ), обладающего способностью опти- мизировать процессы в дыхательной цепи, улучшая энергобаланс в ишемизированной ткани, а также проявляющего антиоксидантные свойства [2][3][4]7]. КоQ 10 (убихинон) синтезируется во всех клетках организма, является составной частью митохон- дриальных мембран и обязательным компонен- том дыхательной электронно-транспортной цепи митохондрий. ...
Article
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Today secondary prevention of coronary heart disease (CHD) is one of the main strategic objectives of the Russian and world healthcare systems. Increasing importance is attached to the use of drugs, optimizing energy exchange of myocardial cells, such as coenzyme Q10 (Qudesan). This article presents the results of research of the effectiveness and tolerability of Qudesan in patients with CHD.
... Such protection is provided by various low-molecular-weight antioxidants, as well as by multiple enzymatic defense systems (Sies 1997). Among the antioxidants, ubiquinone (Quiles et al. 2004) (Marriage et al. 2004) and vitamin E (Moore and Roberts 1998;Pfluger et al. 2004;Stephens et al. 1996) have been found to be particularly important. Selective delivery of synthetic antioxidants to mitochondria has been made possible by attachment of a lipophilic triphenylphosphonium cation to α-tocopherol (MitoVit E) or to ubiquinone (MitoQ) (Smith et al. 2003). ...
Chapter
Fanconi Anemia (FA) is a heterogeneous genetic disorder, with 16 genes so far characterized that function in a common pathway for the maintenance of genomic stability. The clinical manifestations are also heterogeneous, although all patients share progression to bone marrow failure (BMF) and increased predisposition to cancer, particularly acute myeloid leukemia. At the cellular level chromosome instability (CI) is the hallmark of FA, and hypersensitivity of FA cells to the clastogenic effect of DNA crosslinking agents, such as diepoxybutane (DEB), provides a specific diagnostic marker. FA cells are characterized by abnormal accumulation of reactive oxygen species (ROS) and dysfunctional response to oxidative stress (OS). They are in a permanent pro- oxidant state, demonstrated by oxidative DNA damage, increased lipid peroxidation, free iron levels, ROS overproduction, mitochondrial dysfunction, and glutathione (GSH) depletion. The hypersensitivity of FA cells to DEB is a consequence of its OS-related mechanism of cytotoxicity. DEB induces oxidative damage by forming DNA-DNA and DNA-protein crosslinks, associated with GSH depletion and activated mitochondrialapoptotic pathway.The progressive BMF and the increased risk of malignancy associated with FA highlights the importance of understanding how the mechanisms involved in cellular defense against DNA damage fail. It was also shown that dysfunction of FA proteins increases OS damage by down-regulation of antioxidant defense genes. Thus, OS-related CI should be counteracted by other sources of antioxidants, independently of the FA pathway.Recently, it was demonstrated that a cocktail with N-acetylcysteine, a GSH repletor and α-lipoic acid, a mitochondrial nutrient, improved genetic stability in vitro, decreasing CI in cultured lymphocytes from FA patients. These two active thiol antioxidants have already been used in many diseases as pro-glutathione dietary supplements. The clinical relevance of this study is suggested, considering the potential use of small molecules as a prophylactic approach to improve the defense against OS-induced cell damage and, consequently, to delay the clinical symptoms associated with this damage.
... Also, dietary supplementation with CoQ10 may increase mitochondrial activity and function within the developing embryo (Bentov et al., 2010). Subsequently, a superior rate of early bovine embryo cleavage, blastocyst formation, percentage of expanding blastocysts, and a larger inner cell mass as affected by CoQ10 (Marriage et al., 2004). In addition, CoQ10 is antioxidant that has great importance against free radicals (Bentinger et al., 2007). ...
Article
Full-text available
he objective of this study was to evaluate the effect of coenzyme Q10 (CoQ10) and L-carnitine (LC) administration on litter size, ovarian characteristics and in vitro production of rabbit embryos. This study was carried out at the International Livestock Management Training Center (ILMTC), belonging to the Animal Production Research Institute, Agricultural Research Center, Ministry of Agriculture. Total of 36 mature NZW rabbit does (5-6 months of age, 3-3.5 kg LBW as well as 6 NZW bucks (7.5-8 months of age and 3.5-4.0 kg LBW) were used in this study. Does were divided into 3 similar groups, (n=12). The 1 group was control (G1), while does in the 2 and 3 groups were given daily oral dose of 10 mg CoQ10/kg LBW (G2) and 40 mg LC/kg LBW (G3) for 21 days prior to natural mating, respectively. Five does from each group were slaughtered post-mating as oocyte donors for studying the effect of treatments on ovarian characteristics and in vitro maturation and fertilization of oocytes. Immediately after slaughtering, ovaries were removed and oocytes were collected by slicing technique and evaluated, then only compact-cumulus oocytes (COCs) were matured and fertilized in vitro. For the rest number of does in each group (n=7), pregnancy was handy diagnosed by palpation 10-12 days post-mating. Also, litter size and weight at birth up to weaning were recorded. The obtained results showed that, ovarian weight and number of follicles increased (P<0.05) in G2 and G3. Number of bleeding follicles and recovered oocytes increased (P<0.05) only in G2 as compared to G1, however, oocyte recovery rate was not affected by treatment. Frequency distribution of compact and partial denuded oocytes was higher (P<0.05), while that of expanded and denuded oocytes was lower in G2 and G3 as compared to G1. Percentage of oocytes with full expansion (maturation rate) was 80.3 and 79.3% vs. 73.8% and fertilization rate was 67.4 and 66.7% vs. 64.5% in G2 and G3 vs. G ((P≥0.05). Percentage of embryos at morula stage was higher (P<0.05) in G2 and G3 than in G1 (30.3 and 3.1% vs. 20%), respectively. Percentage of embryos at blastocyst stage was 21.2 and 21.4% vs. 15% in G2 and G3 vs. G1, respectively. Litter size of rabbit does was higher (P<0.05) in G2 and G3 than in G1 at birth (7.29 and 6.71 vs. 5.43/doe), at 21 days of age (6.71 and 5.86 vs. 4.43/doe) and at weaning (6.43 and 5.43 vs. 4.14/doe). Mortality rate of kits at birth or weaning was not affected by treatment. Average kit weight at birth was higher (P<0.05) in G2 and G1. However, average kit weight at weaning, average litter weight from birth up to weaning and average litter daily gain from birth up to weaning were higher (P<0.05) in G2 and G3 than in G1. In conclusion, treatment of rabbit does 21 days prior to insemination with CoQ10 at a level of 10 mg/kg LBW or L-carnitine at level 40 mg/kg LBW as daily oral dose is recommended to improve in vitro embryo production and also to increase litter characteristics (size and weight from birth up to weaning) of New Zealand White rabbit does.
... Such protection is provided by various low-molecular-weight antioxidants, as well as by multiple enzymatic defense systems (Sies 1997). Among the antioxidants, ubiquinone (Quiles et al. 2004) (Marriage et al. 2004) and vitamin E (Moore and Roberts 1998; Pfluger et al. 2004; Stephens et al. 1996) have been found to be particularly important. Selective delivery of synthetic antioxidants to mitochondria has been made possible by attachment of a lipophilic triphenylphosphonium cation to α-tocopherol (MitoVit E) or to ubiquinone (MitoQ) (Smith et al. 2003). ...
... Such protection is provided by various low-molecular-weight antioxidants, as well as by multiple enzymatic defense systems (Sies 1997). Among the antioxidants, ubiquinone (Quiles et al. 2004) (Marriage et al. 2004) and vitamin E (Moore and Roberts 1998;Pfluger et al. 2004;Stephens et al. 1996) have been found to be particularly important. Selective delivery of synthetic antioxidants to mitochondria has been made possible by attachment of a lipophilic triphenylphosphonium cation to α-tocopherol (MitoVit E) or to ubiquinone (MitoQ) (Smith et al. 2003). ...
Chapter
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Although major pathological conditions in FA are outcomes of the defects in DNA damage and repair machinery, recent findings suggest that bioenergetic pathways are compromised as well. A few FA proteins have functions that include redox balance, apoptosis, and energy metabolism; and recent data have established respiratory defects in FA cells, proposing that mitochondrial dysfunction (MDF) is involved in FA. This data was further supported by the finding that FA cells have elevated levels of mitochondrial ROS, decreased Mitochondrial Membrane Potential, decreased ATP production, impaired oxygen uptake and changes in the morphology of mitochondria. This was also accompanied by inactivation of enzymes that are essential in the energy production pathway. These findings suggest that mitochondrial activity and its metabolism may be a point of convergence in the pathological manifestations of FA. Mitochondrial dysfunction may thus be considered as an important phenomenon in FA which might account for most of the findings observed in FA’s clinical phenotype. Exploring MDF in FA will provide new facets to the development of diagnostic and therapeutic strategies for FA.
... Do grupy leków zwiększających wydajność łańcucha oddechowego należą m.in. analogi koenzymu Q i pochodne bursztynianu [47,50]. Do grupy leków ograniczających skutki niedotlenienia zalicza się m.in. ...
Article
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Neurons vary widely in shape, size, type of neurotransmitters and number of synapses. Their common characteristic is a very high sensitivity to changes in oxygen concentration. The consequence of hypoxia is to launch a series of biochemical reactions called the ischemic cascade. The term is a bit misleading, because it suggests that there is a succession of events, in a linear fashion. In fact, the ischemic cascade involves very complex processes that take place simultaneously and interact with each other. The key role in neuronal responses to hypoxia is played by changes related to mitochondria, which occur immediately after hypoxia, at the beginning of the ischemic cascade. Disturbances in the mitochondrial functions are recognized as an essential element not only in acute but also in chronic hypoxia, as well as neurodegenerative diseases.
... All three vitamins improve OXPHOS activity. Studies in experimental models suggest the involvement of vitamins E and B2 in the assembly of CoI and of riboflavin in CoIV assembly (43)(44)(45)(46). ...
Article
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The neurobiology of psychiatric disorders is still unclear, although changes in multiple neuronal systems, specifically the dopaminergic, glutamatergic, and gamma-aminobutyric acidergic systems as well as abnormalities in synaptic plasticity and neural connectivity, are currently suggested to underlie their pathophysiology. A growing body of evidence suggests multifaceted mitochondrial dysfunction in mental disorders, which is in line with their role in neuronal activity, growth, development, and plasticity. In this review, we describe the main endeavors toward development of treatments that will enhance mitochondrial function and their transition into clinical use in congenital mitochondrial diseases and chronic disorders such as types 1 and 2 diabetes, cardiovascular disorders, and cancer. In addition, we discuss the relevance of mitochondrial targeted treatments to mental disorders and their potential to become a novel therapeutic strategy that will improve the efficiency of the current treatments.
... Ubiquinone is insoluble in water, and it has a poor intestinal absorption. A recent, reduced formulation, ubiquinol, seems to be better absorbed 28 . ...
Article
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Mitochondrial diseases are a group of rare multisystem disorders characterized by genetic heterogeneity and pleomorphic clinical manifestations. The clinical burden may be heavy for patients and their caregivers. There are no therapies of proven efficacy until now and a multidisciplinary supportive care is therefore necessary. Since the common pathogenic mechanism is the insufficient energy production by defective mitochondria, nutrition may play a crucial role. However, no guidelines are still available. The article reports the current evidence, highlighting nutrition both as support and as therapy. The estimate of nutritional status, energy needs and nutritional behaviors are firstly discussed. Then, we go in-depth on the scientific rationale and the clinical evidence of the use of anti-oxidants and enzyme-cofactors in the clinical practice. In particular, we analyze the role of Coenzyme Q10, Creatine monohydrate, α-lipoic acid, riboflavin, arginine and citrulline, folinic acid, carnitine, vitamin C, K, and E. Every attempt at nutritional intervention should be made knowing patient's disease and focusing on his/her energy and nutrients' requirements. For this reason, clinicians expert in mitochondrial medicine and clinical nutritionists should work together to ameliorate care in these fragile patients.
... Several potential mechanisms through which CoQ10 could improve ovarian functions are proposed, including the antioxidant and antiapoptotic activities of CoQ10, as well as its effects on ATP production in the mitochondria and membrane stabilization (20). CoQ10 improves mitochondrial function and restores energy production by mitochondria (42). Mitochondrial energy production is vital for steroid hormone biosynthesis and normal reproductive function, including oocyte maturation, fertilization, and early embryonic development (43,44). ...
Article
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Context Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women. No study has examined the hormonal and metabolic effects of coenzyme Q10 and/or vitamin E in patients with PCOS. Objective To evaluate the effects of coenzyme Q10 and/or vitamin E on glucose homeostasis parameters and reproductive hormones in women with PCOS. Design/Setting/Participants Randomized double-blind placebo-controlled clinical trial among 86 women with PCOS. Intervention Coenzyme Q10 (CoQ10) or vitamin E or combination for 8 weeks. Main Outcome Measures Glucose homeostasis parameters and sex hormones concentrations. Results We observed that, after adjustment for potential confounders, supplementation with CoQ10 alone or in combination with vitamin E, compared with placebo, had significant effects on fasting blood sugar (FBS), while the effect of vitamin E on FBS was not statistically significant. A significant reduction in homeostasis model assessment of insulin resistance (HOMA-IR) was observed in the CoQ10 and combined groups. CoQ10, vitamin E and Co-supplementation compared with the placebo group, led to decreased serum total testosterone levels (P<0.001). CoQ10 supplementation in combination with vitamin E resulted in a significant improvement in sex hormone-binding globulin (SHBG) compared to other groups (P=0.008). Findings from linear regression analysis revealed that changes in FBS, insulin, and HOMA-IR were predictors of change in FAI (P<0.05). Conclusions In conclusion, CoQ10 with or without vitamin E supplementation among women with PCOS had beneficial effects on serum FBS and insulin levels as well as HOMA-IR and total testosterone levels. However only co-supplementation was able to affect SHBG concentrations.
... α-lipoic acid (3.5-10 mg/kg/d), riboflavin (2.5-5 mg/ kg/d), folinic acid (800 µg daily), l-carnitine (15-50 mg/kg/d), creatine monohydrate (100 mg/kg/d), thiamine (2.5-5 mg/kg/d), niacin (100 mg daily), pantothenic acid (500 mg daily), vitamin B12 (500 µg daily), biotin (30 µg daily), vitamin C (5-10 mg/kg/d, and vitamin E (5-10 mg/kg/d).[81][82][83][84][85][86] Despite lack of evidence, they are used commonly in the management of this group of conditions. ...
... A superior effect of CoQ10 on rate of cleavage, morula/blastocyst formation rate, percentage of expanding blastocysts, and a larger inner cell mass was reported in bovine oocytes by Marriage et al. (2004) and these changes were associated with an increased ATP content in the group of embryos cultured with CoQ10. ROS may originate in the embryo or from extraneous factors. ...
Conference Paper
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This study aimed to evaluate the effect of adding 0 (T1), 0.2 (T2) and 0.4 (T3) mg Coenzyme Q10 (CoQ10)/ml maturation medium (TCM-199) on in vitro maturation (IVM), fertilization (IVF) and embryo culture (IVEC) of NZW rabbit oocytes. Immediately after slaughtering 30 sexually mature does, ovaries were removed and oocytes were collected by slicing. Only compact-cumulus oocytes (COCs) were incubated in CO2 incubator (5% CO2, at 38 C with high humidity, HH) for 20 h. Percentage of oocytes at metaphase II (MII) was determined as maturation rate (MR). IVF was performed of COCs matured with different levels of CoQ10 with spermatozoa capacitated by heparin at 38 C for 24 h in 5% Co2 with HH. Cleavage rate (CR) and fertilized ova were cultured for 5 days at 38 C with 5% CO2 with HH for determining morula (MPR) and blastocyst (BPR) production rates. Results showed that T2 and T3 increased (P< 0.05) the percentage of oocytes at MII (87.17 and 88.99%) and decreased percentage of degenerated oocytes (2.35 and 2.44%) as compared to T1 (75.02 and 7.52%), respectively. CR (70.00 and 72.89 vs. 55.48%), MPR (36.49 and 37.21 vs. 26.35%) and BPR (15.89 and 19.53 vs. 6.45%) were higher (P< 0.05) for T2 and T3 versus T1, respectively. In conclusion, present study cleared that supplementation of maturation medium with CoQ10 at a level of 0.4 mg/ml has improved in vitro maturation, cleavage and developmental potential of rabbit oocytes.
... Another study examined the use of Coenzyme Q₁₀ in the in vitro culture of bovine embryos and found an increase in ATP content in the group of embryos cultured with Coenzyme Q₁₀.These changes were associated with a greater rate of early embryo cleavage, blastocyst formation, percentage of expanding blastocysts, and a larger ICM (Marriage et al., 2004). ...
Conference Paper
Mitochondria are the major energy producers in cells in the form of ATP. Proteins required for mitochondrial function are encoded by both mitochondrial (mtDNA) and nuclear DNA (nDNA) necessitating compatibility between the two genomes. Good quality oocytes containing an optimal number of mitochondria and sufficient levels of ATP produce higher quality blastocysts. Recent data suggests an elevated level of mtDNA may be associated with aneuploidy in blastocysts. In this study, preimplantation embryo development was investigated in relation to mtDNA template number and aneuploidy. ATP levels were measured in blastocysts and linked to aneuploidy. To investigate possible nDNA/mtDNA mismatch, DNA from couples with repeated miscarriage or repeated implantation failure (RM/RIF) was compared with DNA from couples with no history of infertility but who had preimplantation genetic diagnosis (PGD) for monogenic disorders. DNA from both groups was genotyped using SNP arrays. Sequencing of the mitochondrial genome and a set of 53 nuclear-encoded genes important in mitochondrial function was also performed. Further sequencing of the selected nuclear genes in embryos from the PGD group was used to identify variants in the nuclear and mitochondrial genomes associated with poor embryo development. Our data showed that arrested embryos that were euploid had more mtDNA than arrested embryos that were aneuploid. Aneuploidy in blastocysts resulted in variability in ATP levels. When aneuploidy was present in more than ten chromosomes, ATP was almost undetectable. From the sequencing analysis, significantly more couples with RM/RIF (5/12) had partners from the same mtDNA haplogroup compared with the PGD group of couples (1/11). Yet, SNP data analysed by identity by state (IBS) showed no significant differences between partners in couples based on their nDNA even when the HLA region was considered separately. Within the PGD group, the presence of the T haplogroup in the male partner was associated with a smaller percentage of embryos developing to blastocysts. Analysis of embryos from these couples suggested a link with SNPs in nuclear genes (specifically COQ9 and PPARGC1a) encoding mitochondrial proteins which may contribute to poor embryo development due to a disturbance in the electron transport chain or mitochondrial biogenesis respectively. Determining the mitochondrial haplogroups of both parents is a useful tool to investigate potential mismatch between the nuclear and mitochondrial genomes in embryos which may influence their development.
... Positive effects have been shown with CoQ10, ascorbic acid, vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. 168 CoQ10 should be considered essential for anyone on a statin drug, since HMGcoA reductase enzyme reduces CoQ10 production. CoQ10 is essential for mitochondrial function, and deficiency may result in muscle (including heart muscle) and nerve dysfunction. ...
Chapter
This chapter explores the imperative to and the challenges we face in transforming the health system from a disease based system to one based on salutogenesis: creating health. As its hallmark, complementary integrative pain management (CIPM) offers patient- centered care that is inclusive of and collaborative with all appropriate disciplines and strategies— conventional and complementary— for the benefit of the patient. It then follows that it is multidisciplinary and team based. Patient self- actualization and self- care is essential. Its goal is health creation, and it is driven by patient priorities.
... An initial small study demonstrated that intravenous administration of Larginine (500 mg/kg/dose) decreased the severity of stroke like symptoms, enhanced the dynamics of microcirculation, and reduced tissue injury from ischaemia in patients with MELAS . In a large study, a decrease in clinical severity and frequency of stroke like events was demonstrated in MELAS patients, who were treated prophylactically with oral L-arginine (150-300 mg/kg/d) However, randomized controlled trials are required to study the effects of Larginine in treatment of mitochondrial strokes (43) Carnitine is a cellular compound that plays a critical role in the process of fatty acid oxidation and esterification of fatty acids by transferring long-chain fatty acids across the mitochondrial inner membrane as acyl carnitine esters. ...
Article
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Mitochondria are the power factories of the cells and produce ATPby oxidizing reducing equivalents via the respiratory chain. These reducing equivalents originate mainly from the citric acid cycle that also occurs within the mitochondria. Human mitochondria contain their own genetic material in the form of circular DNAthat encodes for only a fraction of the mitochondrial components. The other mitochondrial components are nuclear encoded. Furthermore, the respiratory chain and mitochondrion associated monoamine oxidase are major producers of reactive oxygen radicals. As a result, mutations in mtDNAcan deregulate multiple processes within cells and the balance of this deregulation may contribute to the clinical phenotype Mitochondrial diabetes affects up to 1% of patients with diabetes and is often unrecognized by the physicians. Diabetes and deafness (DAD) or maternally inherited diabetes and deafness (MIDD) or mitochondrial diabetes is a subtype of diabetes which is caused from a point mutation at position 3243 in human mitochondrial DNA, which consists of a circular genome. This affects the gene encoding tRNALeu. Diabetes mellitus is a common feature of mitochondrial disease, but rarely occurs in isolation; other clinical features depend largely on the underlying mtDNAor nuclear DNAmutation. Because mitochondrial DNA is contributed to the embryo by the oocyte and not by spermatozoa, this disease is inherited from maternal family members only. As indicated by the name, MIDD is characterized by diabetes and sensori neural hearing loss. As suggested by the name, patients with MIDD are subject to sensorineural hearing loss. MIDD has also been associated with a number of other issues including kidney dysfunction, gastrointestinal problems, and cardiomyopathy.
... Although shown to be beneficial in treating male oligo-asthenospermia and in cardiology, the clinical use in POR is not abundant (98)(99)(100)(101). Preclinical studies in animals have suggested CoQ10 can protect ovarian reserve, possibly counteracting the physiological ovarian aging by restoring mitochondrial function and augmenting embryo cleavage and blastocyst generation (102)(103)(104). In female infertility, CoQ10 supplementation to COH improved patients' response to ovulation induction and decreased fetal aneuploidy in older patients, between age 35 and 43 (105,106). ...
Article
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The infertile patients with aging ovaries—also sometimes referred to as impending premature ovarian insufficiency (POI), impending premature ovarian failure (POF), or poor ovarian responders (POR), constitute a significant and increasing bulk of the patients appealing to IVF/ART. Different causes have been cited in the literature, among the identified etiologies, including chromosomal and genetic etiology, metabolic, enzymatic, iatrogenic, toxic, autoimmune, and infectious causes. Although the most successful and ultimate treatment of POI/POF/POR patients is egg donation (ED), many, if not most, of these infertile women are reluctant to consent to ED upon the initial diagnostic interview, requesting alternative solutions despite the low odds for success. Despite anecdotal case reports, no unequivocal treatment proved to be successful for these patients in prospective randomized controlled trials. Nevertheless, the addition of growth hormone (GH) to ovarian stimulation in POR with GH deficiency may improve the results of controlled ovarian hyperstimulation (COH) and the IVF success. In patients with autoimmune etiology for POR/POI, the combination of glucocorticosteroids, pituitary-ovarian suppression, and COH may be successful in achieving the desired conception.
... L-Arginine, which is a semiessential amino acid, has been successfully used for treatment of MELAS (Koga et al., 2002). Carnitine, which has a key role in fatty acid metabolism, is used to increase free carnitine levels and is usually used together with CoQ10 (Marriage et al., 2004). Dichloroacetate (DCA) is a lactic acid-lowering molecule that can be targeted to patients with increased lactate or lactic acidosis. ...
Article
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Mitochondrial diseases are a heterogeneous group of disorders that are currently the focus of intense research. The many cell functions performed by mitochondria include ATP production, calcium homeostasis, and apoptosis. One of the unique properties of mitochondria is the existence of a separate mitochondrial genome (mitochondrial DNA, mtDNA) found in varying copy numbers and containing 37 genes, 13 of them encoding proteins. All 13 mitochondrially encoded proteins form part of oxidative phosphorylation complexes through combination with approximately 100 nuclear DNA-encoded proteins. Coregulation of nDNA and mtDNA is therefore essential for mitochondrial function, and this coregulation contributes to the heterogeneity and complexity observed in mitochondrial disorders. In recent times, significant advances have been made in our understanding of mtDNA-related disorders. A comprehensive review of these studies will benefit both current and new researchers and clinicians involved in the field. This review examines the major types of mtDNA-related defects and their pathogenic mechanisms, with a special emphasis on the heterogeneity of mitochondrial disorders. Potential treatment strategies specialized for each of the disorders, including the hormone melatonin and the recent advances in gene therapy, related to their potential applications for the management of the primary mtDNA disorders are also discussed.
... These functions are having practical applications in clinical practice and its use as food/feed supplementation (Krizman et al., 2012). Supplementing coenzyme Q10 is known to provide health benefits, much like nutraceuticals even in healthy individuals (Ramasarma, 2012) and individuals with metabolic disorders like oxidative phosphorylation disorder (Marriage et al., 2004). The CoQ10 also maintains membrane fluidity (Fato et al., 1984) and protects membranous phospholipid against peroxidation (Takayanagi et al., 1980) and in plants photosynthesis (Redfearn, 1966). ...
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The essentiality of nutrients keeps on changing with the advancement in nutritional research and genetic gain. The genetic gain especially in poultry sector is very high which results in increase in nutrient requirement of both the essential and non-essential nutrients. For the rapid growth the requirement of essential nutrients reaches many folds which are in direct relation with the performance, but the requirement for non-essential nutrients is an indirect one. Most of the dispensable amino acids, vitamin C, carnitine, etc. which are being synthesized endogenously are now a days unable to meet the birds requirements that warrants the dietary supply. Another important nutrient is coenzyme Q10 (CoQ10) which endogenously synthesized is now gaining much attention as a supplement for fast growing broilers. The CoQ10 can be termed as multi-functionary as each and every cell in the body needs this but quantity is being high for very active organs like heart, lungs, liver, kidney, etc. They are essential for cellular oxidative phosphorylation and regenerative antioxidant. The supplementation of CoQ10 improved the feed efficiency with reducing the electron leaks from mitochondria and increases total antioxidant capacity. For this property, CoQ10 is widely used in human medicine especially persons suffering from cardiac, neurological disorder, hypercholesterolemic condition and also even in cancer. The CoQ10 in poultry draws first attention when it is found to reducing the ascites mortality in marketable broilers. Thereafter, the advantages of CoQ10 is started to exploit with much attention to ascites, feed efficiency, cholesterol lowering effect nutraceutical and nutrigenomic property both in poultry and swine industry.
... Multiple vitamins and cofactors are used in the treatment of mitochondrial disease, although such therapies are not standardized and multiple variations of treatments exist. [138][139][140][141][142][143][144] Despite empiric rationale for the use of such vitamins or xenobiotics, few trials have explored the clinical effects of these treatments. 145 There is a general lack of consensus regarding which agents should be used, although most physicians prescribe CoQ 10 , L-carnitine, creatine, α-lipoic acid (ALA), and certain B-vitamins. ...
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Purpose: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. Methods: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Results: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease. Conclusion: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.Genet Med 17 9, 689-701.
... 46 The administration of L-carnitine to individuals with mitochondrial dysfunction may minimize the buildup of hazardous acyl compounds. 47 It was reported that L-carnitine treatment benefited a rare instance of podocytopathy linked with type 2 diabetes that suggested acquired mitochondrial cytopathy. 48 ...
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Mitochondria are membrane-bound organelles found in almost all eukaryotic cells. Mitochondria are in charge of mastering and organizing cellular energy production in order to sustain life. Two genomic systems are responsible for mitochondrial biogenesis: nucli�genomes and another set of mitochondrial genes (mtDNA). MtDNA encodes 13 proteins that are required for respiratory chain function. Mitochondria play a role in a variety of cellular processes, including calcium signaling, cell cycle, differentiation, and cell death. Mitochondrial shape indicates good health, and their location in the cell is essential for their function. Mitochondrial dysfunction has been linked to Alzheimer’s disease, metabolic disorders, ischemic brain, heart, and neurodegenerative diseases. In this section, we exemplify the clinical implications of mitochondrial diseases in terms of acquired defects
... It has been found that L-carnitine or acetyl-L-carnitine supplementation may stimulate mitochondrial biogenesis [133][134][135][136]. In MDs, carnitine is generally administered in combination with other vitamins [133,137], although a real benefit of the administration of carnitine in patients affected by MDs remains to be demonstrated with dedicated studies. ...
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Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDs still needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapies using α-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q have met a limited success. Indeed, it would be expected that the employed antioxidants can only be effective if they are able to target the specific mechanism, i.e., involving the central and peripheral nervous system, responsible for the clinical manifestations of the disease. Noteworthily, very often the phenotypes characterizing MD patients are associated with mutations in proteins whose function does not depend on specific cofactors. Conversely, the administration of the antioxidant cocktails might determine the suppression of endogenous oxidants resulting in deleterious effects on cell viability and/or toxicity for patients. In order to avoid toxicity effects and before administering the antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants and cofactors to be administered in MD patients. It would be also worthwhile to check the localization of mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposed cofactor/antioxidant-based therapy.
... CoQ10 is a potent antioxidant frequently used in clinical practice. It potentially prevents the TQ-induced I/R injury because the CoQ, as part of mitochondrial ETC, regulates ATP and ROS synthesis [12,19,[32][33][34]. In aging and chronic arthritis patients, endogenous CoQ10 levels have been shown to significantly decrease, thus inducing mitochondrial vulnerability to I/R processes [19,35]. ...
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Tourniquet (TQ) use during total knee arthroplasty (TKA) induces ischemia/reperfusion (I/R) injury, resulting in mitochondrial dysfunction. This study aims to determine the effects of coenzyme Q10 (CoQ10) and ischemic preconditioning (IPC), either alone or in combination, on I/R-induced mitochondrial respiration alteration in peripheral blood mononuclear cells (PBMCs) and pain following TKA. Forty-four patients were allocated into four groups: control, CoQ10, IPC, and CoQ10 + IPC. CoQ10 dose was 300 mg/day for 28 days. IPC protocol was three cycles of 5/5-min I/R time. Mitochondrial oxygen consumption rates (OCRs) of PBMCs were measured seven times, at baseline and during ischemic/reperfusion phases, with XFe 96 extracellular flux analyzer. Postoperative pain was assessed for 48 h. CoQ10 improved baseline mitochondrial uncoupling state; however, changes in OCRs during the early phase of I/R were not significantly different from the placebo. Compared to ischemic data, IPC transiently increased basal OCR and ATP production at 2 h after reperfusion. Clinically, CoQ10 significantly decreased pain scores and morphine requirements at 24 h. CoQ10 + IPC abolished analgesic effect of CoQ10 and mitochondrial protection of IPC. In TKA with TQ, IPC enhanced mitochondrial function by a transient increase in basal and ATP-linked respiration, and CoQ10 provides postoperative analgesic effect. Surprisingly, CoQ10 + IPC interferes with beneficial effects of each intervention.
... An open-label trial investigated the effects of a 12-month combined regimen including 25 mcg/day of biotin,CoQ10, carnitine, vitamin C, vitamin K1, riboflavin, thiamine, niacin, pyridoxine, pantothenic acid, cyanocobalamin, and folic acid in twelve MD patients. Only one patient showed improvement in energy metabolism and exercise tolerance, while nine patients showed no effects [140]. ...
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Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes(MELAS)syndrome, a maternally inherited mitochondrial disorder, is characterized by its genetic, biochemical and clinical complexity. The most common mutation associated with MELAS syndrome is the mtDNA A3243G mutation in the MT-TL1 gene encoding the mitochondrial tRNA-leu(UUR), which results in impaired mitochondrial translation and protein synthesis involving the mitochondrial electron transport chain complex subunits, leading to impaired mitochondrial energy production. Angiopathy, either alone or in combination with nitric oxide (NO) deficiency, further contributes to multi-organ involvement in MELAS syndrome. Management for MELAS syndrome is amostly symptomatic multidisciplinary approach. In this article, we review the clinical presentations, pathogenic mechanisms and options for management of MELAS syndrome.
... Marriage et al. observed the CoQ 10 but not of B-complex influence on ATP synthesis in peripheral lymphocytes. 13 The authors pointed out that the beneficial effects of single vitamins have often been due to a relative deficiency of the vita-min or to a specific defect in an enzyme that utilizes the vitamin as a cofactor. It is also possible that the time exposure of the cells to thiamine used in our study was too short. ...
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Background. Oxidative stress accompanies neurodegeneration and also causes abnormalities in thiamine-dependent processes. These processes have been reported to be diminished in the brains of patients with several neurodegenerative diseases. Objectives. The aim of this work was to conduct a comparative analysis of the impact of supplemented thiamine on the viability of human B lymphocytes with CAG abnormal expanded huntingtin gene (mHTT) (GM13509) and control, B lymphocytes without mHTT (GM14467) through the following studies: determination of the supplemented thiamine concentrations, which are effective for cell growth stimulation after incubation in thiamine deficit conditions; determination of cell capability to intake the exogenous thiamine; evaluation of exogenous thiamine influence on the profile of the genes related to thiamine and energy metabolism; determination of ATP synthesis and activities of thiamine-dependent enzymes, KGDHC and BCKDHC in the intact cells and upon the exogenous thiamine. Material and Methods. The following methods were used: EZ4U test for cell growth analysis; HPLC for determination of thiamine intake and ATP synthesis, qRT-PCR for evaluation of the gene profiles and spectrophotometric method for KGDHC and BCKDHC activities determination. Results. Maximal cell growth stimulation was observed at 2.5 mM in GM14467 up to 135% of the control culture and at 5.0 mM in GM13509 cells up to 165% of the control culture. Native levels of total ATP and KGDHC and BCKDHC activities in both cell types were comparable and did not changed upon thiamine deficit or supplementation. GM13509 cells showed more of an increase in growth stimulation upon thiamine supplementation than GM14467 cells and this effect was reflected in the increase of intracellular thiamine concentration. Conclusion. The above results and reported changes in expression of GAPDH, IDH1 and SLC19A3 genes observed upon thiamine deficit conditions suggest that intracellular thiamine status and energy metabolism can have a role in HD pathogenesis.
... Coenzyme Q10 is a component of the ETC complex involved in ATP synthesis (201). It acts as an antioxidant in mitochondria and lipid membranes (346). CoQ10 has been suggested to stabilize the mitochondrial membrane in the context of oxidative stress (63,347). ...
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Mitochondria are cellular organelles involved in several biological processes, especially in energy production. Several studies have found a relationship between mitochondrial dysfunction and mood disorders, such as major depressive disorder and bipolar disorder. Impairments in energy production are found in these disorders together with higher levels of oxidative stress. Recently, a number of agents capable of enhancing antioxidant defenses or mitochondrial functioning have been studied for the treatment of mood disorders as adjuvant therapy to current pharmacological treatments. A better knowledge of mitochondrial physiology and pathophysiology might allow the identification of new therapeutic targets and the development and study of novel effective therapies to treat these specific mitochondrial impairments. This could be especially beneficial for treatment-resistant patients. In this article, we provide a focused narrative review of the currently available evidence supporting the involvement of mitochondrial dysfunction in mood disorders, the effects of current therapies on mitochondrial functions, and novel targeted therapies acting on mitochondrial pathways that might be useful for the treatment of mood disorders.
... As an example of how the acetyl-CoA/CoA-SH ratio changes, cells from premature aging mitochondrial DNA mutator mice showed a 10-fold decrease in CoA-SH, but only a 20% decrease in acetyl-CoA [19], once again reflecting the loss of CoA-SH in actively dividing cells when mitochondrial oxidative metabolism is disrupted. However, in a clinical trial where ten patients with mitochondrial disorders were supplemented with a multi-vitamin containing 25 mg/day of pantothenate (vitamin B5), a precursor of CoA-SH, no improvements were found in disease symptoms [20]. are embryonic lethal [39], while ACSS2 knockout mice show only very mild phenotypes [40]. ...
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Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.
... CoQ 10 treatment also failed to improve ptosis and CPEO [230]. Clinical trials also reported little if no benefit in patients with PMD: a study that enrolled 12 patients with different OXPHOS defects failed to demonstrate any clinical improvement upon CoQ 10 treatment, regardless of its ability to promote ATP synthetic capacity in peripheral lymphocytes [231]. A randomized, double-blind, cross-over trial was performed in 30 patients with mitochondrial disorders, who received 1200 mg/day CoQ 10 for 60 days. ...
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Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.
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Poly(2-hydroxyethyl methacrylate) cryogel microbeads were prepared by combining the microchannel and cryo-polymerization methods under frozen condition. The mean diameter of the cryogel microbeads is 924.4 μm with a narrow particle size distribution and the consistency of multi-dispersion coefficient is 0.21. The prepared cryogel microbeads were packed in a chromatography column with diameter of 10 mm and packing height of 91 mm and then they were grafted with N, N-dimethylaminoethyl methacrylate (DMAEMA) monomer. The grafted cryogel microbead bed was used to isolate the adenosine triphosphate (ATP). Chromatographic separation of ATP from the fermentation broths was carried out at the flow velocity of 2 cm·min-1 with 0.01 mol·L-1 HCl as running buffer and 0.03 and 1 mol·L-1 NaCl solutions, respectively as eluting liquid. The high purity ATP was recovered from the Saccharomyces cerevisiae fermentation broth feedstocks containing different contents of ATP, adenosine diphosphate (ADP), adenosine monophosphate (AMP), other impurities and yeast cells. The purities and the recovery ratios of the obtained ATP are about 93.4%~96.9% and 47.0%~82.7%, respectively.
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Although major pathological conditions in FA are outcomes of the defects in DNA damage and repair machinery, recent findings suggest that bioenergetic pathways are compromised as well. A few FA proteins have functions that include redox balance, apoptosis, and energy metabolism; and recent data have established respiratory defects in FA cells, proposing that mitochondrial dysfunction (MDF) is involved in FA. This data was further supported by the finding that FA cells have elevated levels of mitochondrial ROS, decreased Mitochondrial Membrane Potential, decreased ATP production, impaired oxygen uptake and changes in the morphology of mitochondria. This was also accompanied by inactivation of enzymes that are essential in the energy production pathway. These findings suggest that mitochondrial activity and its metabolism may be a point of convergence in the pathological manifestations of FA. Mitochondrial dysfunction may thus be considered as an important phenomenon in FA which might account for most of the findings observed in FA's clinical phenotype. Exploring MDF in FA will provide new facets to the development of diagnostic and therapeutic strategies for FA.
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Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons within the substantia nigra pars compacta. Experimental and clinical data point to a defect of the mitochondrial respiratory chain as one major pathogenetic factor in PD. Although the restoration of mitochondrial respiration and reduction of oxidative stress by coenzyme Q10 (CoQ10) could induce neuroprotective effects against the dopaminergic cell death in PD, these effects of CoQ10 could also improve the dopaminergic dysfunction. Thus, CoQ10 might theoretically exert both neuroprotective and symptomatic effects in PD. Current data from controlled clinical trials are not sufficient to answer conclusively whether CoQ10 is neuroprotective in PD. Moreover, several open and controlled pilot studies on symptomatic effects of CoQ10 revealed inconsistent results. A recent randomized, double-blind, placebo-controlled trial showed no symptomatic effects in PD. CoQ10 is well tolerated and safe as both monotherapy and add-on medication in PD patients. The present review discusses the current knowledge on neuroprotective and symptomatic actions of CoQ10 in PD.
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Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.
Article
Our aim was to analyze biochemical mechanism in regulation and adaptation to feeding with omega-3 and omega-6 PUFA plus coenzyme Q10-based diet in rats. The rats were supplemented with Co Q10 (100 mg/kg b.wt.) for 12 month. Male rats were fed a control, control + Q10, fish oil + Q10 palm oil + Q10 and flax oil + Q10 diet. The learning and tests were monitored in 1st, 3rd, 6th and 12th month after the start of feeding. There was studied the content of lipid peroxidation products in the liver, the level of their potential substrates polyunsaturated fatty acids of omega-3 and omega-6 families and MEC (metabolism effectiveness coefficient) index value. Growth of relative number of hepatocyte in the state of late apoptosis has been detected in rats receiving fish oil, linseed oil and palm oil as compared to the control group at the age of 1 and 3 months. In later period no differences in the invested indices, that can be the result of impact of CoQ10 and adaptation of organism to diet. Proteomic studies of microsomal fraction of hepatocytes in rats have found differences in the manifestation of catalase and cetochrome b5, associated both with age of animals and type of fat in diet. Proteomic analysis of cytosolic fraction revealed the expression of c-type lectin in the later stages of ontogeny. The levels of lipid peroxidation markers obtain to minimum at 3 month in serum and at 6 month in liver. The specific proteomic changes of influence of diet composition were identified during the research.
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There is currently no curative therapy for mitochondrial disorders, although symptomatic measures can be highly effective and greatly improve the quality of life and outcome of these patients. This review highlights potential strategies for the therapeutic management of mitochondrial disorders. Data for this review were identified by searches of MEDLINE, Current Contents, using various relevant search terms. Strategies to establish a therapeutic regimen aim to enhance respiratory chain function, eliminate noxious compounds, shift the heteroplasmy rate, alter mitochondrial dynamics, transfer cytoplasm, and promote gene therapy. Symptomatic measures rely on drugs (e.g., antiepileptics), avoidance of mitochondrion-toxic agents, substitution of blood cells, hemodialysis, invasive measures (such as a pacemaker), surgery (e.g., ptosis correction), physiotherapy, speech therapy, occupational therapy, dietary measures (e.g., ketogenic diet, anaplerotic diet), and the avoidance of mitochondrion-toxic agents (e.g., ozone). With the increasing awareness of mitochondrial disorders, the number of treatment studies is growing and its quality is improving. If high quality studies (high Jadad score) yield statistical significance for end points, a treatment is more reliable than with lower quality studies. Despite the lack of a proven treatment for mitochondrial disorders, a nihilistic attitude toward treatment is not justified. A number of studies are seeking targeted therapies, and highly effective symptomatic measures are available. Copyright © 2015 Elsevier Inc. All rights reserved.
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The elaboration of therapeutic protocols using natural compounds can help in improving the outcomes of many human conditions such as malignant disorders, neurodegenerative diseases, and systemic disorders. Recently, the attention of scientists was more focused on nutraceuticals as potential candidates that can be administered in the management strategy of various pathologies. This rise in nutraceutical applications is due to their relative safety and their pleiotropic effects. Several studies suggest the use of dietary regimens and food-derived substances for the prevention and treatment of many metabolic disorders that affect the central nervous system. The neuroprotective actions offered by these substances are mediated by their pertinent antiapoptotic, antiinflammatory, and antioxidative potentials. Some compounds may also intervene in the promotion of individuals’ health via the regulation of the process of autophagy and via the enhancement of the functionality of intracellular organelles such as mitochondria. Furthermore, healthy diet and the use of dietary supplements can directly influence the functions and the progeny of neural stem cells and the metabolism of microglial cells and can influence the polarization of macrophages in the nervous tissue resulting in better outcomes in some pathologic situations. In this chapter, we review the different roles and applications of nutraceuticals in the treatment of the major brain disorders that can affect human beings.
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Surveys of mitochondrial disease physicians conducted through the Mitochondrial Medicine Society have shown that virtually all providers recommend a variety of dietary supplements as treatments to their patients in an effort to enhance energy production and reduce oxidative stress. In this survey, we asked patients and their parents about their experiences taking these dietary supplements for mitochondrial disease. The survey was disseminated through the North American Mitochondrial Disease Consortium (NAMDC) and the Rare Disease Clinical Research Network (RDCRN) registries and gathered 162 responses. The study ascertained each patient's mitochondrial disease diagnosis, dietary supplements used, adjunct therapy, and effects of the supplements on symptoms and health.
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Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with mitochondrial diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including mitochondrial donation, will offer a better reproductive choice for these women in the future. The treatment of patients with mitochondrial diseases remains a challenge, but guidelines are available to manage the complications of disease. Moreover, an increasing number of therapeutic options are being considered, and with the development of large cohorts of patients and biomarkers, several clinical trials are in progress.
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How to cite this article detail Garg R, Bora NM, Agrawal V, Kumari SS, Devineni K. CoQ10-Mitochondrial Energizer in Ageing Oocytes and female infertility. J South Asian Feder Obst Gynae 2016;8(4):253-255.
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Mitochondria are organelles involved in essential roles in intermediary metabolism, perinatal neurodevelopment, immunity, bioenergetics, neurotransmitter metabolism, among other critical pathways. As such, mitochondrial dysfunction (MD) has deleterious effects with the potential of contributing to neurological diseases or enhancing their morbidity (e.g., autism and schizophrenia). Therefore, accumulation of mitochondrial damage is interpreted as a key element of the development of aging as well as neurodegenerative diseases. With the rise in the prevalence of autism spectrum disorders (ASD), there has been an increased interest in the etiology and contributors of this disorder. MD caused by genetics alone or by gene and environment interactions, may play a role in the etiology of ASD and holds promise for developing future therapies and/or interventions to help manage its symptoms or delaying its onset. Here we explore findings from our research and others analyzing the role of mitochondrial DNA damage as a contributor to ASD morbidity.
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Metabolic diseases are devastating abnormalities that address human lives toward death if they are not correctly managed. Obesity and diabetes mellitus are the prime factors that induce insulin resistance to signaling pathways and increase the risk of cardiovascular diseases. Phytonutrients are the biologically active agents derived from natural sources such as vegetables, fruits, grains, cereals, and medicinal plants, and present the ability to boost the immune system of patients with metabolic disease and also enhance the conditions by the management of lipid profiles, insulin resistance and glucose homeostasis, and chemopreventive events in case of cancer disease. This chapter highlights some phytonutrients that may have issues with the gene and produce healthy and unhealthy interactions. However, the interaction between genetic and environmental factors such as intake of particular healthy and sufficient diet plans with a good lifestyle encourages the development and pathogenesis of diseases of polygenic dietary components. Phytonutrients are critical tools for the modulation of gene expressions involved in signaling pathways and phenotypes linked with metabolic diseases. It is also noted that human health is also affected by dietary nutrients having carcinogens and aflatoxin attached with them and influence the genetic variants. As the knowledge of carcinogen and anticarcinogen increases, nutritional science leads to promising therapeutics for cancer management by healthy diet plans. This chapter has depicted essential aspects of phytonutrients and their interactions with genes in metabolic disease prevention and treatments.
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The main sources of reactive oxygen species (ROS) in cells are mitochondria, whose components would be primary targets of ROS. Both facts are responsible for the key role of these organelles in aging according to the “mitochondrial theory of aging”. Oxidative damage to mitochondrial DNA (mtDNA) is especially important since it would have the longest-term consequences impairing mitochondrial function. This would lead to a decrease in ATP production, but also to an increased ROS generation. In turn, CoQ, which acts as an electron carrier in mitochondria, is an essential factor for cell bioenergetics and an equilibrated CoQ pool is expected to perform a better electron flow adaptation. Moreover, it is a lipid-soluble antioxidant and efficiently prevents oxidation of DNA along with other macromolecules. Other interesting attributed roles include interaction with cell signaling cascades, anti-inflammatory activities and interference with programmed cell death. Due to this pleiotropic effect, most of interventions with CoQ have been focused on multiple processes related to mitochondria. In this sense, its effects have been investigated in mitochondrial diseases and pathological conditions related with aging whose patients have shown a higher frequency of mtDNA alterations. In addition, dietary CoQ also has been tested in combination with different diets rich in particular type of fatty acids due to the role of these in biological membranes and oxidative stress, as well as aging. This chapter aims to review the effect of CoQ on aging and mitochondrial dysfunction, with especial interest in their actions on mtDNA or the consequences of mtDNA alterations.
Article
Mitochondria carry out various essential functions including ATP production, the regulation of apoptosis and possess their own genome (mtDNA). Delivering target molecules to this organelle, it would make it possible to control the functions of cells and living organisms and would allow us to develop a better understanding of life. Given the fact that mitochondrial dysfunction has been implicated in a variety of human disorders, delivering therapeutic molecules to mitochondria for the treatment of these diseases is an important issue. To date, several mitochondrial drug delivery system (DDS) developments have been reported, but a generalized DDS leading to therapy that exclusively targets mitochondria has not been established. This review focuses on mitochondria-targeted therapeutic strategies including antioxidant therapy, cancer therapy, mitochondrial gene therapy and cell transplantation therapy based on mitochondrial DDS. A particular focus is on nanocarriers for mitochondrial delivery with the goal of achieving mitochondria-targeting therapy. We hope that this review will stimulate the accelerated development of mitochondrial DDS.
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Primary mitochondrial disease (PMD) is a group of complex genetic disorders that arise due to pathogenic variants in nuclear or mitochondrial genomes. Although PMD is one of the most prevalent inborn errors of metabolism, it often exhibits marked phenotypic variation and can therefore be difficult to recognise. Current treatment for PMD revolves around supportive and preventive approaches, with few disease-specific therapies available. However, over the last decade there has been considerable progress in our understanding of both the genetics and pathophysiology of PMD. This has resulted in the development of a plethora of new pharmacological and non-pharmacological therapies at varying stages of development. Many of these therapies are currently undergoing clinical trials. This review summarises the latest emerging therapies that may become mainstream treatment in the coming years. It is distinct from other recent reviews in the field by comprehensively addressing both pharmacological non-pharmacological therapy from both a bench and a bedside perspective. We highlight the current and developing therapeutic landscape in novel pharmacological treatment, dietary supplementation, exercise training, device use, mitochondrial donation, tissue replacement gene therapy, hypoxic therapy and mitochondrial base editing. Novel pharmacological agents are under development to treat mitochondrial disease. There is an emerging field of non-pharmacological treatments that have not been comprehensively reviewed in the literature. Rigorous randomised control trials with objective patient-centred primary outcomes are required to establish evidence-based guidelines.
Preprint
Primary mitochondrial disorders (PMDs) are clinically and scientifically complex disorders, making devising therapy an enormous undertaking. However, the formation of national cohorts and extensive use of next-generation gene-agnostic sequencing technologies has resulted in considerable recent breakthroughs in PMD's core understanding. A very exciting new therapeutic arsenal has evolved. Extensive, high-powered, comprehensive clinical studies must now be conducted to identify successful therapies and provide a more definite basis for present therapeutic recommendations. Due to PMD's variability and rarity, these studies will require multicenter collaboration and detailed phenotype-specific subgroup analysis. Since some of the most effective therapies (e.g. exercise, diet, vitamins, even repurposed medications off-patent) have a low financial motive, this is a big challenge. This underscores the necessity for charities and governments to fund evidence-based development that will enable PMD treatments to be moved from bench to bedside. Biomarkers not related to the lives of physicians or patients have typically been used as the major outcomes in clinical trials. Many of these biomarkers have been embraced because they can be statistically examined, rather than capturing the value of a therapy on a patient's quality of life. This stresses the need to co-design patient clinical studies. Any future value studies should employ well-established transnational PMD patient cohorts and globally accepted clinically meaningful and patient-relevant outcome criteria. This will not only aid with patient recruiting, but also provide an international therapeutic efficacy assessment infrastructure.
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Background Clomiphene Citrate is considered the gold-standard for induction of ovulation and has been used for several years to treat PCOS related infertility. Unfortunately, 15-40% of women with PCOS are resistant to Clomiphene Citrate. The study aimed to evaluate potential benefits of adding the active form of Coenzyme Q10 (Ubiquinol) to Clomiphene Citrate compared with Human Menopausal Gonadotropins (hMG) in Clomiphene Citrate resistant PCOS patients. 148 PCOS Patients with Clomiphene Citrate resistance were randomized into two groups (A and B). In group A, controlled ovarian stimulation was done by Clomiphene Citrate 150 mg daily (from 2nd till 6th day of cycle) together with Ubiquinol starting from 2nd day till day of hCG triggering in a dose of 100 mg orally once daily. In group B, hMG was given from 2nd day of the cycle in a dose ranging from 75 to 225 IU. Serial transvaginal ultrasonography was done starting on cycle day 8 and continued till size of leading follicle reaches 18 mm or more then ovulation triggering was done. Thereafter, patients were advised for a timed intercourse (TI) after 36 hours. A blood sample was withdrawn seven days after hCG triggering, for measurement of serum progesterone. If the Patient presented with a missed period for one week, a serum sample was sent for β-hCG. Results There were no statistically significant differences (P > 0.05) between studied groups regarding; number of cases reaching mature follicular size, number of stimulated cycles, endometrial thickness on the day of hCG triggering, mid-luteal serum progesterone, positive serum pregnancy test and clinical pregnancy rate. Conclusions Addition of Ubiquinol to Clomiphene Citrate improved ovarian responsiveness in Clomiphene Citrate resistant patients with results comparable to conventional hMG stimulation protocol.
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Mitochondria are the main organelles responsible for generating cellular energy. The common symptom of mitochondrial disorders is extreme fatigue. The lowered mitochondrial activity owing to lack of chemical transmembrane capacity, changes in the electron transport chain’s function, the maintenance of the inner mitochondrial membrane’s electrical and decrease in essential metabolites transport to the mitochondria. The change in mitochondrial activity is brought about by the reduction of adenosine-5′-triphosphate (ATP) and oxidative phosphorylation. The mitochondrial activity needs regular replacement of natural phytochemicals and supplementations that help to maintain the energy level. The efficacy of oral alternative nutrients like reduced nicotinamide adenine dinucleotide (NADH), alpha-lipoic acid, coenzyme Q10, alpha-lipoic acid carnitine, membrane phospholipids, and other supplements was evaluated in clinical studies and were found effective against mitochondrial disorders. Combinations of these supplements can substantially alleviate weakness and other symptoms associated with mitochondrial disorders in patients. The frequent intake of these nutrients can also help to reduce the onset of various neurological disorders along with mitochondrial dysfunction. These results have significant effects on the welfare of both the civilian and military communities.
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In spite of the advanced researches, preventive measures, and treatment options, cancer remains a growing ailment all over the world and its prevalence is estimated to increase in future. Cellular metabolic alterations have been documented as a hallmark of cancer. Metabolic regulation is an intricately coupled process whose deregulation leads to tumor progression as well as metastasis. In order to thrive in the living system, cancer cells adapt different metabolic pathways (bioenergetics and biosynthesis). They replenish their metabolic demands by switching from normal metabolism to cancer metabolism by the process of metabolic rewiring. Recent researches suggest that starving cancer cells by the use of nontoxic chemical entities can give promising results regarding cancer proliferation. Natural products, especially those of plant origin, offer different chemical scaffolds to target cancer via modulation of multiple cell signaling cascades. Phytonutrients, the secondary metabolites from the plants, constitute edible phytochemicals which are abundantly found in vegetables, whole grains, and fruits. The growing numbers of evidences suggest that phytonutrients exhibit anticancer as well as chemopreventive activities of these bioactive molecules against several cancers by targeting the various significant enzymes of glycolysis, the PPP pathway, TCA cycle, and serine metabolism. This book chapter presents an update for the scientific community about targeting the cancer metabolism by phytonutrients. The alterations in the cancer metabolism in the context of bioenergetics, biosynthesis, and mitochondrial functions have been discussed while presenting the impact of phytonutrients as modulators of potential metabolic effectors in the cancer metabolism.
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Recent developments and future trends in electroanalytical chemistry of antioxidants in pharmaceutical dosage forms are discussed. The advantages of constant-current coulometry and different types of voltammetry in particular rapid response, sensitivity, selectivity, and low detection limits are demonstrated. The special attention is paid to various types of chemically modified electrodes including carbon nanomaterials, nanoparticles of metals, self-organized systems, and their combination. The data presented confirm that electroanalysis can be considered as alternative or additional technique to spectrophotometric and separation methods for determination of antioxidants in pharmaceuticals.
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The bioavailability of coenzyme Q10 (ubiquinone) formulated as an emulsion in a soft gelatin capsule (Ensorb(TM), NDS Pty Ltd, Sydney, Australia) was compared with a hard gelatin powder-filled capsule. The study design was a randomized cross-over trial with a 3-week wash-out period. The study population comprised 23 apparently healthy adults (12 men and 11 women), aged 20-43 years. Each participant took two 50 mg capsules, and blood samples were taken over a period of 36 h. The plasma concentration of coenzyme Q10 peaked between 3 and 4 h after administration of both preparations. The area under the curve (AUC) of Ensorb™ was 927% higher than that observed with the powder-filled capsule (P < 0.0001), suggesting that this emulsion preparation has a higher bioavailability.
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In recent years we have witnessed a major interest in the study of the role of mitochondria, not only as ATP producers through oxidative phosphorylation but also as regulators of intracellular Ca2+ homeostasis and endogenous producers of reactive oxygen species (ROS). Interestingly, the mitochondria have been also implicated as central executioners of cell death. Increased mitochondrial Ca2+ overload as a result of excitotoxicity has been associated with the generation of superoxide and may induce the release of proapoptotic mitochondrial proteins, proceeding through DNA fragmentation/condensation and culminating in cell demise by apoptosis and/or necrosis. In addition, these processes have been implicated in the pathogenesis of many neurodegenerative diseases, which share several features of cell death: selective brain areas undergo neurodegeneration, involving mitochondrial dysfunction (mitochondrial complexes are affected), loss of intracellular Ca2+ homeostasis, excitotoxicity, and the extracellular or intracellular accumulation of insoluble protein aggregates in the brain.
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After fusion of small unilamellar phospholipid liposomes with mitochondrial inner membranes, the rate of electron transfer between membrane dehydrogenases and cytochrome c decreases as the average distance between integral membrane proteins increases, suggesting that electron transfer is mediated through a diffusional process in the membrane plane (Schneider, H., Lemasters, J. J., Höchli, M., and Hackenbrock, C. R. (1980)., J. Biol. Chem. 255, 3748-3756). The role of ubiquinone in this process was evaluated by fusing liposomes containing ubiquinone-10 or ubiquinone-6, with inner membranes. In control membranes enriched with phospholipid only, ubiquinol-cytochrome c reductase and NADH- and succinate-cytochrome c reductase activities decreased proportionally to the increase in bilayer lipid. These decreases were restored substantially in phospholipid plus ubiquinone-supplemented membranes. The degree to which restoration occurred was dependent upon the length of the isoprenoid side chain of the ubiquinone with the shorter chain length ubiquinone-6, always giving greater restoration than ubiquinone-10. It is concluded that electron transfer between flavin-linked dehydrogenases (Complexes I and II) and cytochrome bc1 (Complex III) occurs by independent, lateral diffusion of ubiquinone as well as independent, lateral diffusion of ubiquinone as well as the protein complexes within the plane of the membrane.
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The apparent Km for coenzyme Q10 in NADH oxidation by coenzyme Q (CoQ)-extracted beef heart mitochondria is close to their CoQ content, whereas both succinate and glycerol-3-phosphate oxidation (the latter measured in hamster brown adipose tissue mitochondria) are almost saturated at physiological CoQ concentration. Attempts to enhance NADH oxidation rate by excess CoQ incorporation in vitro were only partially successful: the reason is in the limited amount of CoQ10 that can be incorporated in monomeric form, as shown by lack of fluorescence quenching of membrane fluorescent probes; at difference with CoQ10, CoQ5 quenches probe fluorescence and likewise enhances NADH oxidation rate above normal. Attempts to enhance the CoQ content in perfused rat liver and in isolated hepatocytes failed to show uptake in the purified mitochondrial fraction. Nevertheless CoQ cellular uptake is able to protect mitochondrial activities. Incubation of hepatocytes with adriamycin induces loss of respiration and mitochondrial potential measured in whole cells by flow cytometry using rhodamine 123 as a probe: concomitant incubation with CoQ10 completely protects both respiration and potential. An experimental study of aging in the rat has shown some decrease of mitochondrial CoQ content in heart, and less in liver and skeletal muscle. In spite of the little change observed, it is reasoned that CoQ administration may be beneficial in the elderly, owing to the increased demand for antioxidants.
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We have accumulated evidence that coenzyme Q (CoQ) concentration in the mitochondrial membrane is not saturating for NADH oxidation but is saturating for succinate and glycerol-3-phosphate oxidation. As a result of its kinetic properties CoQ concentration changes must yield changes in respiration rates. This provides a rationale for the reported therapeutic effects of CoQ under conditions when its concentration is decreased, as has been reported in tissues from aged rats; we have failed, however, to detect any specific CoQ decrease in mitochondria from several tissues of aged rats. We can, however, predict from the kinetic bases that CoQ would ameliorate respiration rate also under conditions in which a defect is present in regions not involving the quinone. CoQ incorporation in perfused liver is attempted in order to find experimental systems for investigating its protecting effect. Liposomal CoQ10 perfused in rat livers (where CoQ9 is the main homolog) is incorporated mainly in lysosomes, and its increase in the crude mitochondrial fraction could be mainly ascribed to residual lysosomal contamination. Nevertheless, perfusion with exogenous CoQ10 maintains higher levels of endogenous CoQ9, and higher glutamate oxidation than in controls. In the same system, an oxidative stress by doxorubicin induces mitochondrial changes, including a decrease in endogenous CoQ9 and in respiratory activities. These changes are prevented by concomitant perfusion of liposomal CoQ10.
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We report on the variant phenotypic expression of mitochondrial genotypes in cultured skin fibroblasts and Epstein-Barr virus-transformed lymphocyte cultures from a patient with Pearson syndrome (McKusick no. 260560). Both cell types harbored a heteroplasmic population of normal and deleted mtDNA molecules. The deletion encompassed five tRNA genes and seven genes encoding subunits of cytochrome c oxidase, complex I, and ATPase. Patient skin fibroblasts and lymphocytes harbored 60 and 80% of deleted mtDNA molecules, respectively, and initially displayed defective respiratory chain activities. In both cases, there was a progressive recovery of respiratory chain activities during in vitro cell proliferation. In cultured skin fibroblasts, the loss of the deleted mtDNA molecules accounted for the recovery of normal respiratory chain activities. These features were prevented by allowing respiratory chain-deficient cells to grow in the presence of uridine (200 microM). In Epstein-Barr virus-transformed lymphocytes containing 60% of deleted mtDNA, the recovery of respiratory chain activities was attributable to an increase in the mtRNA translation efficiency rather than to an increased content in mtDNA or mtRNA. The present study suggests that the variant cellular responses to abnormal mitochondrial genotypes might contribute to the tissue-specific expression of mitochondrial disorders in vivo.
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With phosphorus magnetic resonance spectroscopy (31P-MRS) we studied in vivo the effect of six-month coenzyme Q10 treatment on the efficiency of brain and skeletal muscle mitochondrial respiration in six patients with different mitochondrial cytopathies. Before CoQ we found a low phosphocreatine content (average of 25% decrease from controls) in the occipital lobes of all patients. Calculated [ADP] and the relative rate of ATP synthesis were high (as an average, 57% and 16% above control group respectively), whereas the cytosolic phosphorylation potential was low (as an average, 60% of control value). 31P-MRS also revealed an average of 29% reduction of the mitochondrial function in the skeletal muscle of patients compared with controls. After a six-month treatment with 150 mg CoQ10/day all brain variables were remarkably improved in all patients, returning within the control range in all cases. Treatment with CoQ also improved the muscle mitochondrial functionality enough to reduce the average deficit to 56% of the control group. These in vivo findings show the beneficial effect of CoQ in patients with mitochondrial cytopathies, and are consistent with the view that increased CoQ concentration in the mitochondrial membrane increases the efficiency of oxidative phosphorylation independently of enzyme deficit.
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The bioavailability of coenzyme Q10 (ubiquinone) formulated as an emulsion in a soft gelatin capsule (Ensorb™, NDS Pty Ltd, Sydney, Australia) was compared with a hard gelatin powder-filled capsule. The study design was a randomized cross-over trial with a 3-week wash-out period. The study population comprised 23 apparently healthy adults (12 men and 11 women), aged 20-43 years. Each participant took two 50 mg capsules, and blood samples were taken over a period of 36 h. The plasma concentration of coenzyme Q10 peaked between 3 and 4 h after administration of both preparations. The area under the curve (AUC) of Ensorb™ was 927% higher than that observed with the powder-filled capsule (P < 0.0001), suggesting that this emulsion preparation has a higher bioavailability.
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Replicative segregation of mitochondrial DNA (mtDNA) can produce large differences in the proportions of wild-type and mutant mtDNAs in different cell types of patients with mitochondrial encephalomyopathy. This is particularly striking in the skeletal muscle of patients with Kearns-Sayre syndrome (KSS), a sporadic disease associated with large-scale mtDNA deletions, and in sporadic patients with tRNA point mutations. Although the skeletal muscle fibres of these patients invariably contain a large proportion of mutant mtDNAs, mutant mtDNAs are rare or undetectable in satellite cells cultured from the same muscle biopsy specimens. Since satellite cells are responsible for muscle fibre regeneration, restoration of the wild-type mtDNA genotype might be achieved in these patients by encouraging muscle regeneration. To test this concept, we re-biopsied a patient with a KSS phenotype and a mtDNA point mutation in the tRNA leu(CUN) gene and analysed muscle fibres regenerating at the site of the original muscle biopsy. Regenerating fibres were identified by morphological criteria and by expression of neural cell adhesion molecule (NCAM). All such fibers were positive for cytochrome c oxidase (COX) activity by cytochemistry and essentially homoplasmic for wild-type mtDNA, while the majority of non-regenerating fibres were COX-negative and contained predominantly mutant mtDNAs. These results demonstrate that it may be possible to improve muscle function in similar patients by methods that promote satellite cell incorporation into existing myofibres.
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We report a short-term double-blind, crossover study of CoQ10 in 8 patients with mitochondrial encephalomyopathies. Four patients had myoclonus epilepsy with ragged-red fibers syndrome, 3 had mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome, and 1 had chronic progressive external ophthalmoplegia with myopathy. A trend of effectiveness of CoQ10 in several parameters was noted. Fatigability of daily activities was alleviated. The endurance to muscle exercise was augmented. Global muscle strength scored by Medical Research Council scale was increased. The extent of elevation in serum lactate and pyruvate levels after exercise was decreased. However, only the global MRC index score had a statistical significance (p 10 levels were significantly lower in patients than in normal controls before CoQ10 treatment and increased significantly after treatment.
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Several mitochondrial functions decline with age. The contributing factors include, the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.
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Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease associated with point mutations in mitochondrial DNA. The most frequent of these mutations is the G-to-A substitution at nucleotide position 11,778 which changes an evolutionarily conserved arginine with a histidine at position 340 in subunit ND4 of NADH: ubiquinone reductase (respiratory complex I). We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients. Such changes could reflect a substantial loss in the energy conserving function of NADH: ubiquinone reductase and thus explain the pathological effect of the ND4/11,778 mutation.
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Mitochondria were isolated from detergent-treated Epstein-Barr virus-transformed human lymphocytes to examine their potential use in the study of the functional expression of genetic disorders of the respiratory chain. The increase of cytochrome c oxidase activity in the mitochondrial fraction indicated a 6-fold purification of intact mitochondria. Polarographic and spectrophotometric studies revealed that the isolated mitochondria were functionally well preserved. Furthermore, the isolated mitochondria supported an active in organello protein synthesis, which was dependent on the presence of a respiratory substrate generating ATP and was essentially abolished by chloramphenicol or by a specific respiratory chain inhibitor, such as antimycin. Thus, B lymphoblastoid cell lines constitute a valuable source of mitochondria to investigate mitochondrial functions in patients affected by respiratory chain disorders.
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Liver mitochondria from rats fed 1% (w/w) valproic acid for 75 days displayed an approximate 30% decrease in coupled respiration rates with substrates entering the respiratory chain at complexes I and II. Uncoupling the respiration from proton-pumping, or measuring the respiration without complex IV removed this inhibition. The treatment induced a loss of activity of cytochrome oxidase consistent with a decrease in the mitochondrial content of cytochrome aa3. The inhibition induced by long lasting administration of valproate is apparently located at the site of the proton-pumping activity of complex IV. Furthermore, the capacity of electron transport through complex IV, being far in excess of that required for normal functioning in coupled mitochondria, seems to be controlled by the coupling to proton-pumping in which cytochrome aa3 appears to play a major role.
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We report a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes treated with riboflavin and nicotinamide for 18 months, during which time previously frequent encephalopathic spells ceased. To confirm clinical benefit, we withdrew treatment and monitored response with muscle 31P magnetic resonance spectroscopy (MRS) and sural nerve conduction studies. Of three prospectively chosen MRS variables, two changed coincidentally with clinical end points; phosphocreatine (PCr)/adenosine triphosphate recovery rates fell in parallel with sural nerve sensory amplitudes, and a drop in muscle bioenergetic efficiency (relationship of inorganic phosphate/PCr to the accelerating force of contracting muscle) coincided with development of encephalopathy. Investigations revealed a deficiency of respiratory complex I and mutation of the mitochondrial tRNA(Leu)(UUR). We suggest that a defective cellular energy state in mitochondrial disease may be partially treatable and that changes seen in appropriate muscle spectroscopy studies may parallel improvement in brain and peripheral nerve function.
Article
A T-to-C transition mutation at nucleotide position 3,250 in the mitochondrial tRNA(Leu)(UUR) gene was present in a family with mitochondrial myopathy. Two of three muscle biopsies examined had complex I (NADH-ubiquinone oxidoreductase) deficiency. Heteroplasmy of wild and mutant mitochondrial DNA was detected by Nae I digestion of the polymerase chain reaction products with a modified primer. This was found in blood or muscle samples or both from all seven members examined. Similar to the 3,243 mutation in most patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), the new mutation site was located in the dihydrouridine loop and embedded in the binding region of mitochondrial transcription termination factor. Elucidation of the effects of this mutation may help clarify the role of mitochondrial tRNAs and transcription termination.
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During a 4-year period (1984 to 1988), 50 children referred with manifestations of central nervous system or neuromuscular disease combined with hyperlactatemia were subjected to investigations that aimed to identify and characterize children with mitochondrial disorders. Biochemical and morphologic investigations of quadriceps muscle biopsy tissue were done, including oximetric and spectrophotometric analysis of the respiratory chain function, enzyme histochemistry, electron microscopy, and analysis of mitochondrial DNA. A diagnosis of mitochondrial disease was based on the presence of at least two of five criteria: (1) abnormal results of oximetry, (2) abnormal results of spectrophotometry, (3) enzyme histochemical evidence of cytochrome x oxidase deficiency, (4) deletions or point mutations of mitochondrial DNA, and (5) abundant ultrastructurally abnormal mitochondria. With the combined biochemical and morphologic investigation, 20 of the children were found to have mitochondrial disorders. In an additional 10 children a mitochondrial disorder was neither excluded nor verified. Mitochondrial disorders are thus an important cause of central nervous system and neuromuscular disease in children with hyperlactatemia.
Article
We report the electron transfer properties of the NADH:ubiquinone oxidoreductase complex of the respiratory chain (Complex I) in mitochondria of cells derived from LHON patients with two different mutations in mitochondrial DNA (mtDNA). The mutations occur in the mtDNA genes coding for the ND1 and ND4 subunits of Complex I. The ND1/3460 mutation exhibits 80% reduction in rotenone-sensitive and ubiquinone-dependent electron transfer activity, whereas the proximal NADH dehydrogenase activity of the Complex is unaffected. This is in accordance with the proposal that the ND1 subunit interacts with rotenone and ubiquinone. In contrast, the ND4/11778 mutation had no effect on electron transfer activity of the Complex in inner mitochondrial membrane preparations; also Km for NADH and NADH dehydrogenase activity were unaffected. However, in isolated mitochondria with the ND4 mutation, the rate of oxidation of NAD-linked substrates, but not of succinate, was significantly decreased. This suggests that the ND4 subunit might be involved in specific aggregation of NADH-dependent dehydrogenases and Complex I, which may result in fast ('solid state') electron transfer from the former to the latter.
Article
Cultured skin fibroblasts from patients with lacticacidemia were incubated with glucose for 1 h and the lactate and pyruvate production measured. Those patients with increased lactate to pyruvate ratios were further analyzed for the cause of the abnormal redox state. Two categories of patients are described. The first contains patients with either severe or partial cytochrome oxidase deficiency; this group can be broken down further into patients with Leigh's disease, Kearns-Sayre syndrome, and liver-specific cytochrome oxidase deficiency. In this group, the rise in lactate to pyruvate ratio roughly correlated with the severity of the defect. The second patient category had defects located in complex I of the mitochondrial respiratory chain. This is easily demonstrated in the most severely affected patients with the fatal infantile form of the disease. Patients with severe defects in either complex I or cytochrome oxidase had complexes that were only partially assembled. Patients with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes demonstrated only minor changes in redox state and in the behavior of the mitochondrial respiratory chain.
Article
Energy of metabolic oxidations is conserved in the form of ATP by the process of oxidative phosphorylation in mitochondria. The possibility to recognize alterations in the efficiency of oxidative phosphorylation in pathological states and to improve this efficiency in order to correct diseases requires knowledge of the mechanisms controlling the rate of ATP synthesis. This task is hampered by uncertainties still existing on the organization and mechanism of the enzymes carrying out oxidative phosphorylation. The authors have collected experimental evidence that coenzyme Q concentration in the mitochondrial membrane phospholipids in physiologically not saturating for maximal electron-transfer rate: in fact the Km of the redox enzymic complexes, using the oxidized and reduced form of coenzyme Q, for these substrates, are in the range of their concentrations in the membrane. The addition of exogenous coenzyme Q enhances the respiratory turnover above the physiological rate but without reaching theoretical Vmax, owing to the limited miscibility of ubiquinones with the membrane phospholipids. On the contrary, a decrease of ubiquinone content in the membrane lowers electron-transfer activity in a reversible fashion. Taking account that the rate of lateral coenzyme Q diffusion in the membrane does not appear to control electron transfer, it is suggested that only ubiquinone concentration affects the efficiency of oxidative phosphorylation, with interesting pathological and pharmacological implications.
Article
For 2 years we administered high doses of coenzyme Q10 (CoQ) to a patient having mitochondrial encephalomyopathy with cytochrome c oxidase deficiency. Abnormal elevation of the serum lactate per pyruvate ratio and the increased concentration of serum lactate plus pyruvate induced by exercise decreased with CoQ treatment. This therapeutic effect continued for 2 years. 31P nuclear magnetic resonance spectroscopy showed acceleration of the postexercise recovery of the ratio of phosphocreatine to inorganic phosphate in muscle during CoQ treatment. These observations support the beneficial effect of CoQ on the impaired mitochondrial oxidative metabolism in muscle. Also, impaired central and peripheral nerve conductivities consistently improved during CoQ treatment. These results indicate that CoQ has clinical value in the long-term management of patients with mitochondrial encephalomyopathies, even though there are clinical limitations to the effects of this therapy.
Article
Two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS) in one family are reported. Pathological examination of case 1 showed ragged-red fibers, with 7% of the fibers being unstained by cytochrome c oxidase stain, peripheral nerve damage, multiple areas of softening in the cerebrum and midbrain, and spongy changes in the cerebrum, optic nerve and pons. Electron microscopic examination revealed abnormal accumulations of mitochondria in the skeletal muscle, smooth muscle and cardiac muscle. The activity of cytochrome c oxidase in the brain and liver showed a tendency to decrease. In case 2 (maternal aunt of case 1), muscular weakness and peripheral nerve damage improved by treatment with coenzyme Q10. By adding idebenone to the coenzyme Q10 therapy, the EEG and Wechsler's Adult Intelligence Scale (WAIS) improved. Furthermore, in the cerebral spinal fluid (CSF), the protein, lactate, and pyruvate decreased, and the monoamines and monoamine metabolites increased.
Article
A male with mitochondrial myopathy, encephalopathy, lactic acidemia, and strokelike episodes is reported. He had also recurrent episodes of ileus. Muscle biopsy revealed ragged-red fibres. The cytochemistry of cytochrome c oxidase (CCO) showed scattered nonstained fibres, while all muscle fibres were heavily stained by immunocytochemistry using CCO antibody. These findings suggest that partical CCO deficiency may be present in the skeletal muscles of the patient. NADH cytochrome c reductase in the patient's muscle mitochondria was low compared with normal controls (about 26%), although succinate cytochrome c reductase was normal. Coenzyme Q10 administration (90 mg/day) did not improve CSF lactate levels, but did decrease plasma lactate levels. His muscle weakness slightly improved.
Article
We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO). We treated seven patients for 1 year with daily oral administration of 120 mg of CoQ10. Throughout the treatment most of our patients showed a progressive reduction of serum lactate and pyruvate levels following standard muscle exercise and generally improved neurologic functions. The ECG and echocardiogram showed no significant changes in our patients. None of our patients showed any improvement in ptosis and CPEO.
Article
In a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes [MELAS] who had normal mitochondrial enzyme activity, high doses of coenzyme Q10 (CoQ) were administered. Clinical improvement with decreased serum lactate and pyruvate levels was observed. Though the mechanism of action of CoQ is not known, a trial is worthwhile in patients with MELAS.
Article
A small-for-gestational-age female infant born at term developed severe lactic acidosis and died on day 13 of life. Two previous sibs had also died of overwhelming lactic acidosis in the neonatal period. The lactate-to-pyruvate and 3-hydroxybutyrate-to-acetoacetate ratios were elevated at 136 and 42 to one, respectively. The activities of the pyruvate dehydrogenase complex and pyruvate carboxylase in cultured skin fibroblasts were normal but a defect in respiration was indicated by the low rates of conversion of 1-[14C]pyruvate, glutamate, and lactate to 14CO2 in these cells. Skin fibroblast cultures also displayed an elevated lactate-to-pyruvate ratio (72:1) when incubated with glucose as substrate compared to control cell cultures (20:1). When mitochondrial preparations of skin fibroblasts (prepared by digitonin extraction) were tested for their ability to synthesize ATP from a variety of substrates, it was found that those of the patient made adequate amounts of ATP with either succinate or ascorbate/tetramethyl-phenylenediamine as substrate but not with the NAD-linked substrates pyruvate, isocitrate, and palmitoyl carnitine. We propose that this is indicative of a defect in the respiratory chain between NADH and coenzyme Q, for the first time demonstrable in cultured skin fibroblasts.
Article
The contribution of glycolysis and Krebs cycle to the energy provision of human blood lymphocytes in the presence of phytohaemagglutinin has been investigated. Harvesting cultured cells at different times and reincubating them allowed measurement of the potency of metabolic processes at any moment. It was found that the increase in several parameters of carbohydrate metabolism as seen with PHA during 4 h, is more pronounced after 1 or 3 days. During this stimulation oxidation of substrates in mitochondria or nuclei remains tightly coupled to phosphorylation of ADP. It was calculated that under normal conditions 15% of the ATP is formed in glycolysis, and 85% in oxidative phosphorylation. Either of these pathways can provide the energy for the PHA stimulation in short-term experiments. However, both pathways must be active for long-term incubations.
Article
We have investigated the incorporation of ubiquinone homologs from an aqueous medium into intact and ubiquinone-depleted mitochondria and into monolamellar lipid vesicles formed from either pure lecithin or mixed phospholipids. The state of ubiquinones in the aqueous medium was found to be nonmonomeric by the results of EPR spin label studies showing immobilization of nitroxide stearate derivatives in the presence of ubiquinones. The uv spectra of ubiquinone homologs in media of different polarities and in phospholipid bilayers suggest that the incorporated ubiquinones are completely immersed in a hydrophobic medium. The incorporation of ubiquinones into lipid vesicles and mitochondrial membranes was assayed by first removing the nonincorporated quinones by pentane washings and then by measuring the absorbance of the incorporated quinones after extraction with methanol-light petroleum. In a concentration range of added ubiquinones up to 0.3 mm, the incorporation into lipid vesicles and mitochondrial membranes is linear, allowing the calculation of apparent partition coefficients for the ubiquinone homologs between water and the membranes. The partition coefficients largely increased by cosonication of ubiquinones with phospholipids. The incorporation into mitochondrial membranes is about threefold greater than into lipid vesicles. These studies provide a basis for the interpretation of the effects of exogenous ubiquinones in model systems and in membrane-linked activities.
Article
Coenzyme Q10 (vitamin Q10) is biosynthesized in the human body and is functional in bioenergetics, anti-oxidation reactions, and in growth control, etc. It is indispensable to health and survival. The first double-blind trial was with twelve patients, ranging from 7-69 years of age, having diseases including the Duchenne, Becker, and the limb-girdle dystrophies, myotonic dystrophy. Charcot-Marie-Tooth disease, and the Welander disease. The control coenzyme Q10 (CoQ10) blood level was low and ranged from 0.5-0.84 microgram/ml. They were treated for three months with 100 mg daily of CoQ10 and a matching placebo. The second double-blind trial was similar with fifteen patients having the same categories of disease. Since cardiac disease is established to be associated with these muscle diseases, cardiac function was blindly monitored, and not one mistake was made in assigning CoQ10 and placebo to the patients in both trials. Definitely improved physical performance was recorded. In retrospect, a dosage of 100 mg was too low although effective and safe. Patients suffering from these muscle dystrophies and the like, should be treated with vitamin Q10 indefinitely.
Article
This paper briefly summarizes the results of a long-term, open pharmacotherapy trial in 16 patients with well-characterized mitochondrial disease. Outcome measures included repeated clinical evaluation, 31P-NMR spectroscopy and near-infrared spectroscopy. Treated patients appeared to survive longer with less functional disability and medical complications than typically seen in clinical practice.
Article
This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.