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The use of mitochondrial nutrient to improve the outcome of infertility treatment in older patients

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Abstract

We present a hypothesis emphasizing the role of mitochondrial dysfunction in reproductive senescence and suggesting the use of mitochondrial nutrients as an adjuvant treatment in older patients with infertility.

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... Rafieian-Naeini et al. (2022) declared that supplementation of CoQ10 could preserve the liver of quails from histopathological damage of Cd challenge and increase egg quality. As a fat-soluble compound in most cell membranes, CoQ10 plays a pivotal role in electron transport into the respiratory chain (Bentov et al., 2010). CoQ10 is 5 to 10 times more concentrated than other fat-soluble antioxidants, such as vitamin E (Bentov et al., 2010), and acts more efficiently at inhibiting pre-oxidant activities (Chew & Watts, 2004). ...
... As a fat-soluble compound in most cell membranes, CoQ10 plays a pivotal role in electron transport into the respiratory chain (Bentov et al., 2010). CoQ10 is 5 to 10 times more concentrated than other fat-soluble antioxidants, such as vitamin E (Bentov et al., 2010), and acts more efficiently at inhibiting pre-oxidant activities (Chew & Watts, 2004). On the other hand, by reducing α-tocopheroxyl radicals to α-tocopherol, CoQ10 helps to regenerate vitamin E and its functionality (James et al., 2004), showing the indirect effect of CoQ10 on improving TAC. ...
... Coenzyme Q10 is produced in the body and is not necessary to be supplemented; however, exposure to various oxidative stresses such as heavy metals decreases the levels of CoQ10 in tissues, and antioxidant supplementation is required (Bentov et al., 2010 ...
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Background In recent decades, efforts to produce more efficient poultry products have increased due to its high demand. Meanwhile, some stressors have a negative impact on poultry efficiency and reproduction. Cadmium (Cd) is a toxic heavy metal with a high potential for inducing reactive oxygen species. On the other hand, coenzyme Q10 (CoQ10), with antioxidant properties, exerts a free radical‐neutralizing effect on biological systems under stressful conditions. Objectives This study aimed to determine the effect of dietary CoQ10 supplementation on reproductive variables of Cd‐challenged male quails. Methods Two hundred and sixteen 42‐day‐old Japanese quails with a male‐to‐female ratio of 1:3 were randomly divided into three experimental groups (n = 72) and fed by experimental diets from 9 to 13 weeks of age (woa). Treatments included a negative control (NC): feeding basal diet; positive control (PC): feeding basal diet and Cd administration (1 mg per 100 g body weight at 10 and 11 woa); and CdQ10: dietary supplementation of CoQ10 (900 mg per kg diet) and Cd administration. At 10 and 13 woa, liver and testis, cloacal gland index, sera concentration of malondialdehyde (MDA) and testosterone, total antioxidant capacity (TAC), alanine aminotransferase (ALT), testicular histology, mRNA abundance of Hsp70 and fatty acid profile of testis, as well as hatchability and fertility, were measured. Results Liver and testis weights, cloacal gland index, serum concentration of testosterone, ALT, MDA, TAC, mRNA abundance of HSP70, hatchability, and fertility were not affected by the treatments. However, Cd administration decreased seminiferous tubule diameter and seminiferous epithelium thickness (SET) in the PC group compared to the NC group (p < 0.05). The proportion of saturated fatty acids (SFA) in testis tissue was increased, and the proportion of PUFA and n‐3 to n‐6 PUFA ratio was decreased in the PC group compared to the NC group (p < 0.05). In addition, CoQ10 supplementation ameliorated the effect of Cd on decreasing SFA and increasing n‐3 to n‐6 PUFA ratio proportions. Conclusions In conclusion, Cd exerts several adverse effects on reproductive‐associated variables; some, but not all, of them are mitigated by CoQ10 supplementation.
... Moreover, in metabolically active granulosa cells mitochondrial dysfunction might contribute to oxidative stress, cell damage and apoptosis [7]. Mitochondria are a sensitive site for oxidative damage being both a source and a target of reactive oxygen species (ROS), conditions associated with infertility, such as ageing that might exacerbate this process [8]. ...
... Among the effectors and regulators of oxidative stress in the follicular fluids attention should be drawn on lipoprotein composition and mitochondrial activity in the oocyte and granulosa cells. In particular, the production of energy for the metabolic requirement of the oocyte is provided solely by mitochondria that are present in remarkable number in mature oocytes, much higher than other cell types with elevated cellular requirements such as muscle cells and neurons [8,32]. The oocyte mitochondrial pool remains unaltered up to 40 years before follicle maturation, therefore from a "mitochondrial senescence" point of view these cells present similarities with non-replicative cells such as neural cells. ...
... This phenomenon might underlie increased oxidative stress and abnormal embryonic development. In this frame nutrition is known to play a role in the modulation of reproductive performances [8,33], nonetheless our understanding of the role of micronutrients, trace elements and vitamins are still lacking. In this study we evaluated the effect of oral administration of Coenzyme Q10, an endogenous lipophilic mitochondrial nutrient with important antioxidant activity in the lipoprotein environment. ...
Article
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Background: The target of the reduced fecundity with aging is the oocyte. The follicular fluid and its components are strongly linked with the environment of the maturing oocyte. The aim of the present study was to evaluate CoQ10 bioavailability in follicular fluids after oral supplementation and its possible implication in oocyte maturation. Methods: Fifteen female partners of infertile couples, aged 31⁻46, undergoing IVF-ET and taking 200 mg/day oral CoQ10 were compared to unsupplemented patients. CoQ10 content, its oxidative status and total antioxidant capacity were evaluated also in relation to oocyte maturation indexes. Results: CoQ10 supplementation produced a significant increase in follicular content and a significant improvement of its oxidative status. Follicular fluid total antioxidant capacity highlighted a significant decrease in patients supplemented with CoQ10, specially in women >35 years. CoQ10 supplementation was associated with a significant decrease in total antioxidant capacity of fluid from follicles containing mature oocyte, moreover CoQ10 oxidative status was also significantly reduced but in follicles containing immature oocyte. Conclusions: Our observation leads to the hypothesis that the oral supplementation of CoQ10 may improve follicular fluid oxidative metabolism and oocyte quality, specially in over 35-year-old women.
... ROS are normally generated through oxidative phosphorylation in the mitochondria [29,30]. However, high levels of ROS can damage many cellular biomolecules, such as carbohydrates, lipids, proteins, and DNA, which is thought to be involved in aging-related pathologies [22]. ...
... Mitochondria are the major source of energy in all eukaryotic cells. It has been suggested that mitochondrial dysfunction results in chromosomal anomalies during mitosis, influencing the developmental competence of pre-implantation embryos [22,29,30]. Mitochondrial functions depend on the maintenance of membrane potential [2]. ...
Article
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The success rate of assisted reproductive technology is closely correlated with maternal age. Reproductive aging pathologies are frequently caused by impaired DNA repair, genomic instability, and mitochondrial dysfunction. Several reports have shown that resveratrol can prevent age-related diseases by improving mitochondrial function. Improved blastocyst development and mitochondrial output by dichloroacetic acid (DCA) supplementation were reported in aged mice. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has significant effects on implantation rates in women with previous miscarriages. Therefore, this study was conducted to observe how those compounds influence the developmental and the reproductive potential of aged oocytes. BDF1 female mice at 58-62 weeks old were used for this study. MII oocytes were fertilized and cultured in MRC media supplemented with or without resveratrol (0.5 μM), GM-CSF (2 ng/ml) or DCA (1.0 mM). The addition of resveratrol, GM-CSF or DCA tended to increase blastocyst development and pregnancy rates. Supplementation with resveratrol significantly increased the pregnancy and implantation rates (p < 0.05). Moreover, resveratrol decreased reactive oxygen species production and increased mitochondrial membrane potential. These results suggest that the addition of resveratrol can increase pregnancy outcomes in women of advanced maternal age.
... Also, CoQ10 can regenerate α-Tocopherol from the radical α-Tocopherol [13]. Coenzyme Q10 is an isoprenylated benzoquinone that transfers electrons in the mitochondrial respiratory chain of the cell such as spermatozoa or each other cell type [14,15]. Several studies performed on in vitro cooled semen of different species such as bull [16], ram [17] and horse [13,18] they were proved that including CoQ10 to semen extender improved sperm quality. ...
... It occurs when ROS overcome the natural antioxidant defenses [16]. Mitochondrial DNA, unlike nuclear DNA, does not contain histones or introns, under oxidative stress, making the mitochondrial DNA more vulnerable to mutations and deletions, which in turn, leading to apoptosis of the cell [14]. In studies performed on bovine [28] and human [29] showed that supplementation CoQ10 to semen extender prevented chromatin fragmentation at ambient temperature for 5-6 h of incubation. ...
... 15 Uno de los factores predictores de éxito de los procederes de reproducción asistida, es la calidad embrionaria, la cual, a su vez, depende fundamentalmente de la edad. 16 Se ha demostrado una alta frecuencia de alteraciones cromosómicas en embriones de mujeres mayores de 35 años, 16,17 que redunda en fallas de fertilización, generación de embriones anormales, menor desarrollo embrionario in vitro, menor implantación, incremento de abortos precoces, y por lo tanto, menor fecundidad. [15][16][17][18] Nuestros resultados coinciden con varios estudios, 17,18 ya que encontramos una mayor edad (35,38±3,99 años) en las pacientes en las que se obtuvieron embriones de mala calidad, y fue estadísticamente significativa la diferencia entre los dos grupos investigados. ...
... 16 Se ha demostrado una alta frecuencia de alteraciones cromosómicas en embriones de mujeres mayores de 35 años, 16,17 que redunda en fallas de fertilización, generación de embriones anormales, menor desarrollo embrionario in vitro, menor implantación, incremento de abortos precoces, y por lo tanto, menor fecundidad. [15][16][17][18] Nuestros resultados coinciden con varios estudios, 17,18 ya que encontramos una mayor edad (35,38±3,99 años) en las pacientes en las que se obtuvieron embriones de mala calidad, y fue estadísticamente significativa la diferencia entre los dos grupos investigados. Este resultado se comprobó en el estudio multivariado, en el cual se encontró una influencia significativa de la edad como factor independiente sobre la calidad embrionaria, y se demostró que a medida que aumenta la edad, la probabilidad de tener embriones de buena calidad es de 0,96, con un IC de 0,81 a 0,99. ...
... Frequency of antioxidant supplementation among women of childbearing age is noted to have increased in recent years due to claims of improved fertility potential (Bentov et al. 2010;O'Connor et al. 2016;Florou et al. 2020). For example, coenzyme Q10 (CoQ10) is an antioxidant that supports cellular growth and energy production (Rodríguez-Varela and Labarta 2021; HealthLink BC 2022). ...
Article
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Dietary supplements including vitamins, minerals, and natural health products are commonly consumed by those aiming to optimize fertility and pregnancy outcomes. The aim of this survey was to describe supplementation practices among individuals who were pregnant or trying to conceive in Vancouver, Canada. An online survey was conducted among 500 individuals who were pregnant (n = 250) or trying to conceive (n = 250). Participants met a substantial proportion of vitamin and mineral recommendations through supplements alone. Exceptions included calcium, magnesium, and choline, with median (interquartile range (IQR)) supplementation doses reported by those who were pregnant and trying to conceive, respectively, of: 250 (200 and 250 mg) and 250 (200 and 250 mg), 50 (50 and 75 mg) and 50 (50 and 90 mg), and 53 (10 and 150 mg) and 55 (10 and 100 mg), as compared to perinatal recommendations of 1000 mg/day (calcium), 350 mg/day (magnesium), and 450 mg/day (choline). Conversely, median (IQR) doses of folate reported by those who were pregnant and trying to conceive, respectively, were: 1000 (780 and 1000 µg) and 1000 (800 and 1000 µg), with ∼70% overall (337/471) reporting doses ≥1000 µg (the tolerable upper intake level). Most participants (451/500; 90%) reported supplementation with a prenatal multivitamin; of these, 83% reported that supplementation occurred daily. Overall, as diet was not considered, we cannot ascertain whether recommendations for calcium, magnesium, and choline were met through the combination of supplements and foods; however, we believe that additional supplementation with choline may be required to meet recommendations in pregnancy. Excessive folate supplementation has been previously identified as a concern throughout North America; here, we provide further evidence for excessively high doses consumed via supplements.
... Being an active antioxidant, it is involved in the regeneration of the endogenous antioxidant system, i.e. superoxide dismutase which in turn impedes lipid peroxidation (Navas et al., 2007). It is a stronger antioxidant than alpha-tocopherol and can regenerate alphatocopherol from alpha-tocopherol radicals (Bentov et al., 2010;Nogueira et al., 2015). ...
Article
This study aimed to determine the effects of Coenzyme Q10 (CoQ10) in the freezing medium on functional and oxidative stress parameters and in vitro fertilization (IVF) rate of buffalo sperm. Collected samples were relocated to the laboratory for initial evaluation, gentle dilution in extenders, cooling (4°C, 2 h), equilibration (4°C, 4 h), packaging (straws, 0.5 mL), programmable freezing, and thawing (37°C, 30 s). Statistical analysis depicted that adding CoQ10 (100 μM) in a freezing medium caused a significant augmentation in total motility (%), average path, and straight‐line velocities (μm/sec) of buffalo sperm than control. Adding CoQ10 (100 μM) improved sperm progressive motility, rapid velocity, and functional parameters (%) compared to the control and 10 μM of CoQ10. Moreover, CoQ10 in a freezing medium caused a significant augmentation in seminal plasma catalase (U/mL) and glutathione reductase (GSH; nmol/10 ⁹ ) at 100 μM than control and other treatments. CoQ10 inclusion (100 μM) ameliorates seminal plasma superoxide dismutase (U/mL), glutathione‐S‐transferase (GST; nmol/mL/min) fructose (μg/mL), and ATP (nmol/million) than control. Furthermore, CoQ10 at 100 μM improved seminal plasma glutathione peroxidase (μM) levels than control, 10 μM, and 20 μM. Lastly, hydrogen peroxide (H 2 O 2; nM) production was significantly lower at 100 μM than at control and 10 μM. CoQ10 (100 μM) caused a significant augmentation in the un‐capacitated pattern followed by a reduction in the capacitated pattern, and apoptosis‐like changes (%) than control, and other treatments, whereas viability was increased than control and other treatments. CoQ10 (100 μM) significantly improved the IVF rate in comparison with control, CoQ10 at 10 μM, and 20 μM groups. In conclusion, the addition of CoQ10 (100 μM) in the freezing medium can improve the quality and in vitro fertility of post‐thawed buffalo semen via its antioxidative effect. Further studies are needed to evaluate the effect of CoQ10 on the in vivo fertility of buffalo bull semen.
... CoQ10 is found in the inner mitochondrial membrane and acts as a membrane-associated antioxidant that prevents lipid peroxidation and DNA damage [56] . Furthermore, CoQ10 enhances adenosine triphosphate generation in the eggs, promotes chromosomal segregation and ROS counteraction, and slows reproductive aging, all of which contribute to oocyte quality and fertilized oocyte activation, leading to future embryo development [57,58] . Ma et al. [59] discovered that supplementation with 50 mmol/L CoQ10 during IVM enhanced the rates of oocyte maturation and decreased postmeiotic aneuploidies in older women. ...
Article
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In vitro maturation (IVM) is considered a potential assisted reproductive technology that is a safer and simpler alternative to conventional in vitro fertilization. It is primarily used in patients with impaired oocyte maturation and for the treatment of infertile women who are at risk of fertility loss. In addition, IVM is currently used mainly in polycystic ovarian syndrome patients with a high ovarian response and is still considered an experimental option in fertility preservation. Producing highly competent oocytes during IVM is considered a key step in the success of in vitro production (IVP) of embryos. Some factors, such as culture medium conditions and other supplements, have a significant impact on oocyte IVM performance. One of the known disruptors of oocyte developmental competence in IVP is oxidative stress (OS), which is caused by an imbalance between the production and neutralization of reactive oxygen species (ROS). In vitro conditions induce supraphysiological ROS levels due to exposure to an oxidative environment and the isolation of the oocyte from the follicle protective antioxidant milieu. Given the importance of OS in oocyte competence, the establishment of standardized antioxidant IVM systems is critical for improving the overall success of IVP. This review focuses on the main antioxidants tested to protect oocytes against OS in IVM.
... CoQ10 is found in the inner mitochondrial membrane and acts as a membrane-associated antioxidant that prevents lipid peroxidation and DNA damage [56] . Furthermore, CoQ10 enhances adenosine triphosphate generation in the eggs, promotes chromosomal segregation and ROS counteraction, and slows reproductive aging, all of which contribute to oocyte quality and fertilized oocyte activation, leading to future embryo development [57,58] . Ma et al. [59] discovered that supplementation with 50 mmol/L CoQ10 during IVM enhanced the rates of oocyte maturation and decreased postmeiotic aneuploidies in older women. ...
Article
In vitro maturation (IVM) is considered a potential assisted reproductive technology that is a safer and simpler alternative to conventional in vitro fertilization. It is primarily used in patients with impaired oocyte maturation and for the treatment of infertile women who are at risk of fertility loss. In addition, IVM is currently used mainly in polycystic ovarian syndrome patients with a high ovarian response and is still considered an experimental option in fertility preservation. Producing highly competent oocytes during IVM is considered a key step in the success of in vitro production (IVP) of embryos. Some factors, such as culture medium conditions and other supplements, have a significant impact on oocyte IVM performance. One of the known disruptors of oocyte developmental competence in IVP is oxidative stress (OS), which is caused by an imbalance between the production and neutralization of reactive oxygen species (ROS). In vitro conditions induce supraphysiological ROS levels due to exposure to an oxidative environment and the isolation of the oocyte from the follicle protective antioxidant milieu. Given the importance of OS in oocyte competence, the establishment of standardized antioxidant IVM systems is critical for improving the overall success of IVP. This review focuses on the main antioxidants tested to protect oocytes against OS in IVM.
... At the same time, it removes oxygen free radicals from tissues and body fluids, prevents protein and lipid peroxidation, and protects mitochondria from oxidative stress-induced damage [7,8]. The CoQ10 content in human tissues decreases with age, resulting in compromised oocyte quality and development [9,10]. Researchers have pointed out that CoQ10 supplementation can not only preserve the follicle pool, promote oocyte maturation and ovulation, but also restore mitochondrial gene expression in oocytes and improve mitochondrial activity [6]. ...
Article
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Abstract Purpose To investigate the effects of coenzyme Q10 (CoQ10) and transcutaneous electrical acupoint stimulation (TEAS) pretreatment on pregnancy in patients with poor ovarian response (POR). Methods A total of 330 POR patients who were pretreated with CoQ10 or CoQ10 combined with TEAS before their in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) cycles and who were not pretreated were selected and divided into CoQ10 group (group A, n = 110), CoQ10 + TEAS group (group B, n = 110) and control group (group C, n = 110). For patients with 2 or more transfer cycles, only the information of the first cycle was included. Ovarian function, response to gonadotropin (Gn) stimulation, and pregnancy outcomes of the three groups were compared in the IVF/ICSI-ET cycles. Results After pretreatment, basal FSH, total Gn dosage and duration were comparable among the three groups (all p-value > 0.05), basal E2 in group B decreased significantly compared with the control group (p = 0.022). Endometrial thickness on the human chorionic gonadotropin (hCG) day, antral follicle counts (AFC), the numbers of oocytes, metaphase II (MII) eggs and excellent embryos in the two pretreatment groups were significantly increased compared with group C (all p-value
... Preclinical animal study by Bentov et al showed that Coq10 increased reproductive life time of female mice by about 30% and animals that received more Coq10, produced more and healthier eggs and showed improved ovarian response. 9 Yahya et al conducted study on clomiphene resistant PCOS women receiving Coq10 200 mg/day for two months in addition to clomiphene citrate 100 mg/day (for 5 days in each induction month). 10 There was post treatment decrease in serum free testosterone, LH, LH: FSH ratio and serum glutathione and a ovulation rate of 76.5%. ...
Article
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Background: Polycystic ovary syndrome (PCOS) is the largest single cause of anovulatory infertility. PCOS is associated with oxidative stress. Coenzyme q10 (Coq10) is an antioxidant that protects the mitochondria from damage caused by either insulin resistance or oxidative free radicals. The objective of the study was to compare the effect of combined Coq10 and letrozole than of letrozole alone for ovulation induction in women with PCOS.Methods: This open label parallel design randomized controlled trial study was conducted on 80 infertile women with PCOS selected for ovulation induction. Eligible women were randomized either to combined Coq10 and letrozole (40 patients, 83 cycles) or letrozole alone (38 patients, 91 cycles). The outcome measures were mature follicles, adequate endometrial thickness, ovulation and pregnancy.Results: Mature follicles (≥18-25 mm) were significantly higher in women given Coq10 at 2nd (74.2% vs 31.3%) and 3rd cycles (83.3% vs 28.6%). Adequate endometrial thickness was significantly higher in women given Coq10 in second (90.3% vs 56.3%) and third cycle (94.4% vs 47.6%). When Coq10 was added to letrozole, ovulation rates were significantly higher (87.1% vs 53.1% in second cycle), (83.3% vs 38.1%, in third cycle). Cumulative pregnancy was 2.37 times (95% CI 1.03-5.48) higher in women having Coq10 in addition to letrozole for ovulation induction. Conclusions: Coq10, as an adjuvant to ovulation induction with letrozole improves ovarian response, ovulation and pregnancy in PCOS women. Combination of Coq10 and letrozole can be tried successfully before a more complicated and expensive treatment such as gonadotrophins and laparoscopic ovarian drilling.
... In fact, mitochondria have been suggested to be a promising biomarker for IVF outcomes (Kim and Seli, 2019;Legro, 2019). Furthermore, the possibility of overcoming mitochondria dysfunction to improve oocyte quality and age-related infertility has become the goal of numerous studies (Bentov et al., 2010;Ben-Meir et al., 2015, 2019Cagnone et al., 2016;Labarta et al., 2019). ...
Article
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RESEARCH QUESTION: Female age is the single greatest factor influencing reproductive performance and granulosa cells are considered as potential biomarkers of oocyte quality. Is there an age-effect on the energy metabolism of human mural granulosa cells? DESIGN: Observational prospective cohort and experimental study including 127 women that underwent in vitro fertilization cycles. Women were allocated to two groups: a group of infertile patients aged over 38 years and a control group comprising oocyte donors aged less than 35 years. Individuals with pathologies that could impair fertility were excluded from both groups. Following oocyte retrieval, cumulus and granulosa cells were isolated and their bioenergetic properties (oxidative phosphorylation parameters, rate of aerobic glycolysis and adenine nucleotide levels) were analyzed and compared. RESULTS: Human mural luteinized granulosa and cumulus cells present high rates of aerobic glycolysis that cannot be increased further when mitochondrial ATP synthesis is inhibited. Addition of follicular fluid to the experimental media is necessary to reach the full respiratory capacity of the cells. Granulosa cells from aged women present lower mitochondrial respiration, although mitochondrial mass is not decreased, and lower aerobic glycolysis than those from young donors. The concurrent decrease in the two energy supply pathways leads to a decrease in the cellular ATP levels. CONCLUSIONS: Human mural luteinized granulosa cells exhibit a reduction in their energy metabolism as women age that is likely to influence female reproductive potential.
... In recent years, the demand for assisted reproductive technologies (ART) is constantly increasing, with more women encountering challenges with fertility. The reproductive capacity of the couple declines with age [1] and female aging is known to be associated with an impairment of the ART procedure's outcome, with a worsening of number and quality of oocytes, a reduced embryo quality and an increased incidence of miscarriages and embryo aneuploidy [2]. Chromosomal abnormalities depend on spindle instability, telomere shortening, chromosome misalignment, and mitochondrial dysfunction [3,4]. ...
Article
Background Resveratrol display’s positive effects on follicle growth and development in preclinical studies while there is scantly information from clinical trials. The aim of this study was to evaluate the biological and clinical impact of a resveratrol-based multivitamin supplement on intracytoplasmatic sperm injection (ICSI) cycles. Methods A randomized, single-center controlled trial conducted at the University Center of Assisted Reproductive Technologies involving 101 women infertile women undergoing ICSI cycles was conducted. A pretreatment with a daily resveratrol based nutraceutical was administered to the Study Group; Control Group received folic acid. The primary outcomes were the number of developed mature follicles (>16 mm), total oocytes and MII oocytes recovered, the fertilization rate and the number of cleavage embryos/blastocysts obtained. Secondary endpoints were the duration and dosage of gonadotropins, the number of embryos for transfer, implantation, biochemical, clinical pregnancy rates, live birth and miscarriage rates. Results A significantly higher number of oocytes and MII oocytes were retrieved in the Study Group than in Control Group (p = .03 and p = .04, respectively). A higher fertilization rate (p = .004), more cleavage embryos/patient (p = .01), blastocytes/patients (p = .01) and cryopreserved embryos (p = .03) were obtained in the Study Group. No significant differences in biochemical or clinical pregnancy, live birth, and miscarriage rates were revealed, but a trend to a higher live birth rate was revealed in the Study Group. Conclusions A 3 months period of dietary supplementation with a resveratrol-based multivitamin nutraceutical leads to better biological effects on ICSI cycles. Trial registration number ClinicalTrials.gov registration identifier: NCT04386499
... 15 Many previous studies evaluating antioxidants as mitochondrial nutrients suggest that abnormalities resulting from mitochondrial dysfunction may be counteracted by the use of antioxidants. 29 For cellular energy production, CoQ10 is an indispensable component for the transport of electrons in the mitochondrial respiratory chain. Moreover, CoQ10 is an antioxidant that restores lipid peroxide levels and the activities of enzymatic and non-enzymatic antioxidants to near normal. ...
Article
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Methotrexate (MTX) has toxic effects on the uterus and ovaries via oxidative stress. Coenzyme Q10 (CoQ10) is an important component in electron transport in the mitochondria and an antioxidant in cellular metabolism through the inhibition of lipid peroxidation. The aim of this study was to investigate the preventive effects of CoQ10 on MTX-induced utero-ovarian damage and oxidative stress in rats. In this experimental study, 30 albino Wistar female rats were divided randomly into three groups. Once a day for a month, 10 mg/kg of CoQ10 was orally administered to the rats in the MTX+CoQ10 group, while the same volume of olive oil was administered orally to the other two groups. One hour thereafter, 20 mg/kg of MTX was injected intraperitoneally into the rats in the MTX and MTX+CoQ10 groups; the remaining group was the control. At the end of the month, biochemical and histopathologic examinations were performed on the extracted uteri and ovaries. In the uterine ovarian tissues of the animals in the MTX group, there was an increase in oxidative stress mediators and a decrease in antioxidant and anti-inflammatory mediators, but these trends were reversed in the MTX+CoQ10 group, demonstrating the antioxidant effects of CoQ10. MTX leads to oxidative stress-related ovarian and uterine injury, and CoQ10 may be useful for protecting ovarian and uterine tissue from such injury.
... The fact that the oxidative stress model phenocopies the chromosome and spindle defects observed in oocytes from reproductively aged mice, which are also fully rescued by MitoQ and BGP-15, is further support that oxidative stress contributes to the aging oocyte phenotype. A number of studies have investigated the effects of nontargeted, cytoplasmic antioxidants on oocyte quality of reproductively old or obese mice with generally positive results (Bentov et al., 2010(Bentov et al., , 2014Liu et al., 2013;Ben-Meir et al., 2015;Boots et al., 2016). However, directly targeting the source of ROS using mitochondriatargeted molecules, such as MitoQ and BGP-15, is clearly highly effective in restoring MMP as well as spindle function and chromosome alignment in oocytes from old mice. ...
Article
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Study question: Do mitochondria-targeted therapies reverse ageing- and oxidative stress-induced spindle defects in oocytes from mice and humans? Summary answer: Exposure to MitoQ or BGP-15 during IVM protected against spindle and chromosomal defects in mouse oocytes exposed to oxidative stress or derived from reproductively aged mice whilst MitoQ promoted nuclear maturation and protected against chromosomal misalignments in human oocytes. What is known already: Spindle and chromosomal abnormalities in oocytes are more prevalent with maternal aging, increasing the risk of aneuploidy, miscarriage and genetic disorders such as Down's syndrome. The origin of compromised oocyte function may be founded in mitochondrial dysfunction and increased reactive oxygen species (ROS). Study design, size, duration: Oocytes from young and old mice were treated with MitoQ and/or BGP-15 during IVM. To directly induce mitochondrial dysfunction, oocytes were treated with H2O2, and then treated the MitoQ and/or BGP-15. Immature human oocytes were cultured with or without MitoQ. Each experiment was repeated at least three times, and data were analyzed by unpaired-sample t-test or chi-square test. Participants/materials, setting, methods: Immature germinal vesicle (GV) stage oocytes from 1-, 12- and 18-month-old mice were obtained from preovulatory ovarian follicles. Oocytes were treated with MitoQ and/or BGP-15 during IVM. GV-stage human oocytes were cultured with or without MitoQ. Mitochondrial membrane potential and mitochondrial ROS were measured by live-cell imaging. Meiotic spindle and chromosome alignments were visualized by immunofluorescent labeling of fixed oocytes and the 3-dimensional images were analyzed by Imaris. Main results and the role of chance: MitoQ or BGP-15 during IVM protects against spindle and chromosomal defects in oocytes exposed to oxidative stress and in oocytes from aged mice (P < 0.001). In human oocytes, the presence of MitoQ during IVM promoted nuclear maturation and had a similar positive effect in protecting against chromosomal misalignments (P < 0.001). Limitations, reasons for caution: Our study identifies two excellent candidates that may help to improve fertility in older women. However, these potential therapies must be tested for efficacy in clinical IVM systems, and undergo thorough examination of resultant offspring in preclinical models before utilization. Wider implications of the findings: Our results using in-vitro systems for oocyte maturation in both mouse and human provide proof of principle that mitochondrially targeted molecules such as MitoQ and BGP-15 may represent a novel therapeutic approach against maternal aging-related spindle and chromosomal abnormalities. Study funding/competing interest(s): The project was financially supported by the National Health and Medical Research Council and Australian Research Council, Australia. U.A.-Z. was supported by the Iraqi Higher Education and Scientific Research Ministry PhD scholarship and O.C. was supported by TUBITAK-1059B191601275. M.P.M. consults for MitoQ Inc. and holds patents in mitochondria-targeted therapies. R.L.R. is an inventor on patents relating to the use of BGP-15 to improve gamete quality. Trial registration number: N/A.
... The germinal disc (GD) of the bird oocyte is structurally and functionally equivalent to the mammalian oocyte and contains important components, such as BMP15 and GDF9 that are integral for fertilization and early embryonic development (Elis et al., 2007;Han et al., 2015). Adenosine triphosphate is required for spindle formation and chromosomal alignment during oocyte maturation, as well as for the processes of fertilization and early embryo development (Bentov et al., 2010). Enriching the diets of the aged hens with mitochondrial nutrients, such as CoQ10, may result in an improvement in ATP production and oocyte quality, which can subsequently increase egg hatchability rates. ...
Article
The aim of this study was to evaluate the effects of supplementary CoQ10 in the diets of aged broiler breeder hens on productive and reproductive variables. A total of 128 hens (44 weeks of age) were randomly assigned to one of 16 groups (eight hens per group). The hen-groups (with equal mean egg production and egg weight) were randomly assigned to one of four diet-groups to provide four pen/groups per treatment. There was no CoQ10 supplementation or supplemental amounts of either 300, 600 or 900 mg CoQ10/kg added to the basal diet. Egg production, weight, and mass were determined weekly. To assess fertility, hatchability, and sperm penetration (SP) rate, the hens were artificially inseminated on a weekly basis (from 47 to 54 weeks of age). The hens were weighed and killed at the end of the experiment for evaluation of the ovarian morphology, oviduct histology, utero-vaginal junction (UVJ) total antioxidant capacity (TAC), and Pdss2, GDF9, and BMP15 mRNA transcript abundances in the germinal disc regions. The results indicated that there was a linear response curve to increasing amounts of supplemental dietary CoQ10 on fertility, hatchability of eggs, SP rates, TAC of the UVJ, fold height and surface epithelia of the magnum and isthmus, and abundance of GDF9, BMP15 and Pdss2 mRNA transcripts in the germinal disc region. In conclusion, the findings of the present study indicate diet supplementation with CoQ10 had beneficial effects on the productive and reproductive variables of aged hens.
... Dietary supplementation with CoQ10 can improve mitochondrial function in oocytes and developing embryos and may decrease the aneuploidy rate in human oocytes. [113] CoQ10 is a key enzyme in energy production and a major cellular antioxidant [114] that aids in the transport of electrons in the mitochondrial respiratory chain and is essential for the stability of complex III. [115] ALA is a coenzyme involved in mitochondrial metabolism. ...
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Fertility disorders have become a growing problem worldwide. It is well known that female fertility decreases with age, previous studies suggested that the age-related decline in female fertility potential was largely due to decrease in oocyte quality and mitochondrial dysfunction. Mitochondria play a crucial role during the process of oocyte maturation. Mitochondrial genetic, numerical and structural defects occur in oocyte aging process, mitochondrial abnormalities are believed to contribute to age-related infertility. Improvement of the mitochondrial function can lead to better fertility outcomes, and application of mitochondria replacement strategy or mitochondrial transfer to age-related infertility will be possible in the future. This review paper, we are trying to discuss current understanding about age-related changes in oocyte quality and mitochondrial dysfunction.
... In studies conducted on birds, it has been shown that TAC decreases during ageing, and that the addition of antioxidants, such as a-Tocopherol to diets improves TAC levels [22]. Coenzyme Q10 is a potent antioxidant that is even stronger than a-Tocopherol and can also regenerate a-Tocopherol from a-Tocopherol radicals [23,24]. ...
Article
In numerous studies it has been suggested that targeting mitochondria with specific compounds could efficiently inhibit various conditions associated with oxidative stress. The treatment of aged roosters with compounds such as coenzyme Q10 (CoQ10), may improve their reproductive performance by providing protection from oxidative stress. Therefore, this study was performed to assess the effect of supplemental dietary CoQ10 on the testicular function and fertility of aged broiler breeder roosters. A total of 36 roosters (47 weeks of age) were randomly divided into dietary treatments containing either 0, 300 or 600 mg CoQ10/kg diet. Three birds were allocated to each of four replicate groups in each dietary treatment. Between 47 to 54 weeks of age, ejaculates were obtained weekly from the three roosters in each replicate group. Samples in a replicate were pooled and analyzed as a single sample. Between 51 and 54 weeks of age, seminal plasma total antioxidant capacity (TAC), alanine amino transferase (ALAT) and aspartate amino transferase (ASAT) levels were assessed. Fertility, hatchability, and sperm penetration (SP) rates were likewise evaluated. Seminal volume, sperm concentration, sperm plasma membrane functionality, sperm plasma membrane integrity, seminiferous tubule diameter and seminiferous epithelium thickness exhibited quadratic increases in response to increasing levels of dietary CoQ10. Respectively, the 429.19, 433.33, 464.50, 613.50, 392.78 and 447.99 mg/kg dietary concentrations of CoQ10 provided the best results for each of the aforementioned variables. Also, other seminal traits, as well as testosterone concentration, fertility, and SP rates, displayed linear increases in response to the increasing levels of CoQ10. Dietary supplementation of CoQ10 linearly decreased seminal plasma ALAT and ASAT and linearly increased seminal plasma TAC. In conclusion, CoQ10 supplementation in the diet (a minimum of 300 mg CoQ10/kg diet) has the potential to improve the reproductive performance of aged broiler breeder roosters.
... In mammals, an initial oocyte has 500 mtDNA copies, and the MII oocyte has 150,000-700,000 mtDNA copy numbers [78]. The number of mtDNA copies increases by more than 30 times during oocyte maturation [79]. The wide range of mtDNA copy number indicates a high degree of variability among individual human oocytes. ...
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Abstract Polycystic ovary syndrome (PCOS) is a prevalent hormonal disorder of premenopausal women worldwide and is characterized by reproductive, endocrine, and metabolic abnormalities. The clinical manifestations of PCOS include oligomenorrhea or amenorrhea, hyperandrogenism, ovarian polycystic changes, and infertility. Women with PCOS are at an increased risk of suffering from type 2 diabetes; me\tabolic syndrome; cardiovascular events, such as hypertension, dyslipidemia; gynecological diseases, including infertility, endometrial dysplasia, endometrial cancer, and ovarian malignant tumors; pregnancy complications, such as premature birth, low birthweight, and eclampsia; and emotional and mental disorders in the future. Although numerous studies have focused on PCOS, the underlying pathophysiological mechanisms of this disease remain unclear. Mitochondria play a key role in energy production, and mitochondrial dysfunction at the cellular level can affect systemic metabolic balance. The recent wide acceptance of functional mitochondrial disorders as a correlated factor of numerous diseases has led to the presupposition that abnormal mitochondrial metabolic markers are associated with PCOS. Studies conducted in the past few years have confirmed that increased oxidative stress is associated with the progression and related complications of PCOS and have proven the relationship between other mitochondrial dysfunctions and PCOS. Thus, this review aims to summarize and discuss previous and recent findings concerning the relationship between mitochondrial dysfunction and PCOS.
... CoQ10 has been shown to play a role in the treatment of mitochondrial disorders in animals. 7 It has been suggested that pre-treatment with CoQ10 leads to improved ovarian response and embryo quality in young women undergoing in-vitro fertilization procedure to improve the decreased ovarian reserves. 8 It has been observed that the metabolic and endocrine dysfunctions in patients with PCOS improve with the maintenance of CoQ10 as it ameliorates insulin and lipid metabolism. ...
Article
Objective: To investigate the effect of coenzyme Q10 (CoQ10) supplementation on ovulation induction (OI) and intrauterine insemination (IUI) outcomes in polycystic ovary syndrome (PCOS) patients with clomiphene citrate (CC) failure or resistance. Material and Methods: A total of 130 nulliparous infertile patients diagnosed with PCOS were included in this prospective study. The first group of patients who were unable to conceive after the first treatment with CC received CoQ10 treatment at a dosage of 100 mg/bid for one month (study group). The other group (control group) received no treatment with CoQ10. The two groups were compared with each other in terms of cycle characteristics and success of the treatment for the subsequent three months. Results: The study group included 66 patients and the control group involved 64 patients. No statistically significant differences were observed between the groups in terms of age, body mass index (BMI), and infertility type. All the study participants had previously received similar medical treatments for infertility. Duration of infertility was significantly longer in the study group as compared to that in the control group (3.4 ±1.5 vs. 2.9 ±1.1 years). Cumulative pregnancy rates were observed to be 18 (27.3%) and 21 (32.8%) in the study and control group, respectively. Conclusion: Short term CoQ10 supplementation was not found to be an effective adjuvant therapy for cumulative pregnancy rates in young infertile women with PCOS who have undergone ovulation induction with intrauterine insemination. Yet, this treatment may prove to be effective on some other subgroup of women. Keywords: Clinical pregnancy; clomiphene citrate failure; coenzyme Q10; infertility; PCOS
... In order to overcome this issue, the researchers are now searching for some natural supplements or mixture of supplements to combat against the infertility problems. Indeed, the nourishment of mitochondrialgametes by means of nutrient supplementation has also been testified to be active in many cases (Bentov et al., 2010). In this regard, mitochondrial metabolism of both female and male gametes plays a vital role (May-Panloup et al., 2007). ...
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Precise natural anti-oxidative compounds have facilitated the research of infertile gametes and the development of novel bio-therapeutics, especially the molecules that are based on the reduction of oxidative stress, such as L-carnitine (LC). In addition to, the defect in the functioning of sperm mitochondrial and the decreasing seminal antioxidant ability due to aging, its essential role in permitting the mitochondrial import and oxidation of long chain fatty acids is worthy. Therefore, current study was designed to investigate the effects of dietary LC on semen quality, seminal antioxidant activity, and their implications for the fertility in aged cocks for 12 wk. Supplementation of the feed with two different doses of LC (50 and 150 mg/kg body weight/day) for 12 wk showed significantly increased in the reproductive activity of cock, in comparison to the control group. Seminal analysis showed that supplementation of LC significantly increased (P < 0.05) the sperm motility, concentration, livability, semen quality factor, seminal malondialdehyde concentration , catalase, and glutathione peroxidase activities. In addition, addition of LC significantly increased (P < 0.05) the plasma concentration of testosterone and prostaglandin E2 but posed no significant effect on the concentration of follicle-stimulating hormone. Furthermore , the findings of artificial insemination showed significant increased (P < 0.05) in the percentage of fertility in LC groups, while the percentage hatchability and mortality remained unchanged. Immunohistochem-istry analysis revealed that LC significantly increased (P < 0.05) the testicular immunopositivity of MT1 and MT2. Moreover, the administration of LC to the aged cocks enhanced (P < 0.05) GnRH1 and GnRHR mRNA levels when compared with untreated cocks. The results of the present study suggest that LC treatment of aged cocks increases the seminal antioxidant enzymes and sexual hormones levels, which may improve the semen quality by increasing the expression of GnRH1 and melatonin receptors (MT1 and MT2) activities. Collectively , LC could be a suitable feed supplementation to increase reproductive activities through enhancing semen quality in aging cocks.
... Many attempts have been made to improve the mitochondrial function of oocytes, including mitochondrial nutrient supplements (Bentov, Esfandiari, Burstein, & Casper, 2010). However, the clinical efficacy of such attempted enhancements remains unsatisfactory. ...
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Female fertility declines dramatically over the age of 35 due to age‐related decreases in oocyte quality and quantity. Although mitochondrial transfer promises to be a technology that can improve the quality of such age‐impaired oocytes, the ideal mitochondrial donor remains elusive. In the present study, we aimed to identify whether aged adipose‐derived stem cells constitute an excellent mitochondrial donor that would improve the quality of aged mouse oocytes. We showed that aging significantly impaired the mitochondrial function in mouse oocytes, but did not significantly affect the mitochondrial function of adipose‐derived stem cells. However, the mitochondrial transfer from aged adipose‐derived stem cells did not mitigate the poor fertilization and embryonic development rates of aged oocytes.
... Клиническая значимость всех этих патологических изменений в конечном итоге заключается в том, что их сочетание в значительной степени ускоряет развитие и прогрессирование атеросклероза и сердечно-сосудистых заболеваний, которые являются самой частой причиной смертности среди населения высокоразвитых стран [7][8][9]. ...
... Tsai and colleagues performed a prospective cohort study that revealed lower levels of mitochondria deletion in CCs were associated with higher pregnancy rates in IVF cycles [51]. Therefore, enhancing mitochondrial biogenesis may result in an improvement of oocyte and embryo quality and, subsequently, better pregnancy outcomes because increased mitochondrial energy production may decrease chromosomal aneuploidies, improve embryo cleavage, and reduce cytoplasmic fragmentation [52]. Our previous studies showed that DHEA could increase mitochondrial function and activity, and reduce apoptosis and cell necroptosis in CCs and human granulosa cell line [3,4,53]. ...
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Mitochondrial dysfunction is related to reproductive decline in humans, with consequences for in vitro fertilization (IVF). We assessed whether dehydroepiandrosterone (DHEA) could regulate mitochondrial homeostasis and mitophagy of cumulus cells (CCs) in poor ovarian responders (PORs). A total of 66 women who underwent IVF treatment at the Reproductive Medicine Center of Kaohsiung Veterans General Hospital were included in this study. Twenty-eight normal ovarian responders (NOR) and 38 PORs were enrolled. PORs were assigned to receive DHEA supplementation (n = 19) or not (n = 19) before IVF cycles. DHEA prevents mitochondrial dysfunction by decreasing the activation of DNM1L and MFF, and increasing MFN1 expression. Downregulation of PINK1 and PRKN occurred after DHEA treatment, along with increased lysosome formation. DHEA not only promoted mitochondrial mass but also improved mitochondrial homeostasis and dynamics in the CCs of POR. We also observed effects of alterations in mRNAs known to regulate mitochondrial dynamics and mitophagy in the CCs of POR. DHEA may prevent mitochondrial dysfunction through regulating mitochondrial homeostasis and mitophagy.
... This reduction could be reversed by administration with mitochondrial nutrients. Dietary supplementation with CoQ10 may increase mitochondrial activity in compromised oocytes (Bentov et al., 2010). ...
Article
The oocyte achieves its developmental competence through the lengthy process of folliculogenesis. It can therefore potentially be exposed to various stressors while enclosed in the follicle. Oocyte maturation relies mainly on maternal sources. These include nuclear, cytoplasmic, and molecular maturation, which involve DNA and RNA organization. Maternal transcripts are dominant through the first embryonic cleavages, up until embryonic genome activation. Thus, it is suggested that any perturbations during oocyte storage, in particular of the maternal transcripts, might lead to genetic and/or epigenetic changes, which might be further expressed in the developing embryo. The review discusses the effects of three representative stressors—environmental heat stress, endocrine‐disrupting compounds (phthalates), and inflammatory stress (mastitis)—shown to be involved in reduced fertility. The review highlights the carryover response from the oocyte to the developing embryo; it includes intracellular and molecular disruptive mechanisms with an emphasis on maternal transcripts. The review provides insights into the oocyte’s cellular and molecular responses with an emphasis on the effects of various stressors on the maternal (nuclear and mitochondrial) transcripts and the association with embryonic development. A comparison between stressors might clarify, at least in part, a few open questions. For instance, (a) whether stress‐induced alterations share the same mechanism and if so (b) whether this mechanism involves alterations of maternal transcripts; (c) whether stress‐induced alterations in the maternal transcript are further expressed at the developing blastocyst stage, that is, after embryonic genome activation.
... One of the more frequent mtDNA deletions is the ''common deletion''of 4977 base pairs, almost a third of the whole mtDNA genome. This deletion was shown to have a high prevalence in unfertilized oocytes and oocytes from elderly women [9] ( Figure 2). ...
Article
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Free circulating Nucleic Acids and Infertility
... It protects the stability of the cell membrane, DNA from free radicals induced oxidative damage and helps recycling of vitamin E and maintain healthy energy levels (El-Tohamy et al., 2012). Dietary supplementation with CoQ10 may increase mitochondrial activity within the cells (Bentov et al., 2010). ...
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Aim of the present study was to evaluate the effect of treatment of L-carnitine or coenzyme Q10 on growth performance, liver and kidney functions, thyroid hormones, and economic feed efficiency of growing rabbits fed diet supplemented with propolis. Total of 60 weaned New Zealand white rabbits (5 wk of age and 702.58±12.70 g live body weight) were divided into 3 similar groups (20 in each, 10 from each sex). Rabbits in the 1 st group were fed commercial pelleted diet (CPD) without any treatment and served as control (G1). While, rabbits in the 2 nd and 3 rd groups were fed CPD (18% CP, 13% CF and 2800 Kcal/kg) supplemented with 0.5 g prop olis (PR)/kg and orally administrated with 10 mg CoQ10/kg LBW (G2) and 40 mg L-carnitine (LC)/kg LBW (G3), respectively. Feeding rabbits was ad. Libitum, while drinking water nipples were present in each cage. From 5-13 wk of age as an experimental period, rabbits were treated by each combination twice weekly. Average of body weight (LBW), feed intake (FI) and daily gain (ADG), rate of feed conversion (FC) and viability, relative growth rate (RGR) and performance index (PI) were determined. At 13 weeks of age (end of experiment), blood samples were taken from 3 slaughtered males in each group to determine total proteins (TP), albumin (AL), creatinine (CR), urea (UR), cholesterol (CH), HDL, LDL and triglycerides (TG) concentrations, AST and ALT activity and T3 and T4 concentrations. Weights of liver, kidney and body fat were recorded. Small samples from liver and kidney tissues were taken to examine the histological structure. Results showed that final LBW, ADG, FI, RGR and FCR were not significantly affected by treatment, although these parameters tended to be the highest in G2, moderated in G3, and the lowest in G1, being higher in male than female rabbits. All growth performance parameters was not significantly affected by the interaction between treatment and sex of rabbits. Effect of treatment was not significant on absolute and relative weight of the liver and kidney. Effects of treatment on concentrations of TP, AL, GL, CR, UR, CH, HDL, LDL, TG, T3, T4, AL/GL ratio and ALT activity in blood serum were not significant, while AST activity reduced (P<0.05) in G2 and G3 than in G1. Based on the histological examination, rabbits in treated groups (G2 and G3) showed normal liver and kidney functions. Average weight of abdominal fat was higher (P<0.05) in G1 than in G2 and G3. Subcutaneous fat as absolute or relative weight of total fat was not significant. In conclusion, treatment of growing rabbits during marketing period (5-13 wk of age) with a combination of propolis and coenzyme Q10 or L-carnitine twice/week led to functional liver and kidney with normal lipid profile. These findings were associated with remarkable improvement in growt h performance parameters.
... It has been demonstrated that embryo implantation potential is correlated with the ATP content of the embryo [19]. Preliminary data demonstrated that CoQ10 treatment, but not ALA and resveratrol, was associated with increased oocyte numbers and oocyte mitochondrial activity parameters, similar to oocytes from young ICR controls [20]. On the contrary to ALA administration alone, the combination of ALA and inositols not only modulate insulin plasma levels but also, thanks to inositols, improved the reproductive pathways thanks to an effect on FSH signal transduction [7,11]. ...
Article
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Alpha-Lipoic acid (ALA) is a natural antioxidant synthetized by plants and animals, identified as a catalytic agent for oxidative decarboxylation of pyruvate and α-ketoglutarate. In this review, we analyzed the action of ALA in gynecology and obstetrics focusing in particular on neuropathic pain and antioxidant and anti-inflammatory action. A comprehensive literature search was performed in PubMed and Cochrane Library for retrieving articles in English language on the antioxidant and anti-inflammatory effects of ALA in gynecological and obstetrical conditions. ALA reduces oxidative stress and insulin resistance in women with polycystic ovary syndrome (PCOS). The association of N-acetyl cysteine (NAC), alpha-lipoic acid (ALA), and bromelain (Br) is used for prevention and treatment of endometriosis. In association with omega-3 polyunsaturated fatty acids (n-3 PUFAs) with amitriptyline is used for treatment of vestibulodynia/painful bladder syndrome (VBD/PBS). A promising area of research is ALA supplementation in patients with threatened miscarriage to improve the subchorionic hematoma resorption. Furthermore, ALA could be used in prevention of diabetic embryopathy and premature rupture of fetal membranes induced by inflamation. In conclusion, ALA can be safely used for treatment of neuropatic pain and as a dietary support during pregnancy.
... Therefore, we suggest that massive production of ROS might cause decreased mitochondrial activity and negatively influence preimplantation embryonic development. According to a previous studies, mitochondrial activity is correlated with two-cell blocks, and the use of mitochondrial nutrients, such as coenzyme Q10, could improve the outcome of infertility treatment in older patients [54,55]. ...
Article
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In vitro follicle growth (IVFG) is an emerging fertility preservation technique, which can obtain fertilizable oocytes from an in vitro culture system in female. This study aimed to compare efficiency of the most widely used two-dimensional follicle culture methods [with or without oil layer (O+ or O− group)]. Preantral follicles were isolated from mice and randomly assigned. Follicles were cultured for 10 days and cumulus-oocyte complexes harvested 16–18 hours after hCG treatment. Follicle and oocyte growth, hormones in spent medium, meiotic spindle localization, expression of reactive oxygen species (ROS), mitochondrial activity, and gene expression were evaluated. In follicle growth, survival, pseudoantral cavity formation, ovulation, and oocyte maturation were also significantly higher in O+ group than O− group. Hormone production was significantly higher in follicles cultured in O+ than O−. There were no significant differences in mRNA expression related to development. On the other hand, the level of ROS was increased while the mitochondrial activity of in vitro grown matured oocyte was less than in vivo matured oocytes. In conclusion, follicle culture with O+ group appears to be superior to the culture in O− group in terms of follicle growth, development, oocyte growth, maturation, and microorganelles in oocyte.
... This reduction could be reversed by administration with mitochondrial nutrients. Dietary supplementation with CoQ10 may increase mitochondrial activity in compromised oocytes (Bentov et al., 2010). ...
Article
Stress can affect reproductive performance of lactating cows by targeting the ovarian pool of follicles and their enclosed oocytes. Among the documented stressors are heat stress (i.e., high temperature-humidity index) as well as environmental and food toxins. Oocytes collected during the hot season are of lower quality than those collected in the winter, expressed by reduced oocyte maturation and developmental competence. A similar pattern has been reported for oocytes exposed to endocrine-disrupting chemicals. Whereas the underlying mechanism might differ among stressors, accumulating evidence suggests that stress-induced impairment of oocyte developmental competence involves alterations in mitochondrial functioning. Within the oocyte, mitochondria are involved in ATP generation, calcium homeostasis, regulation of cytoplasmic reduction-oxidation, signal transduction, and apoptosis. Summer heat stress is strongly associated with alterations in mitochondrial distribution and alterations in mitochondria membrane potential. Heat stress impairs the expression of mitochondrion-associated genes, in particular those related to mitochondrial DNA transcription and replication and encoding oxidative phosphorylation complexes for ATP production. Reduction of ATP levels below the required threshold is suggested to compromise the progression of oocyte maturation and, subsequently, embryonic development. Another mechanism associated with mitochondrial function is the increase in reactive oxygen species (ROS), which has been documented in oocytes exposed to heat stress or environmental toxicants. Oxidative phosphorylation in mitochondria is the major source of ROS. Under physiological conditions, ROS are essential for nuclear maturation; however, disequilibrium between ROS production and antioxidative capacity might lead to DNA damage and apoptosis. The current review provides new insights into the oocyte's cellular and molecular responses to stress with an emphasis on the mitochondria. It discusses some strategies to mitigate the effects of stress on the mitochondria, such as incorporation of coenzyme Q10-a key component of the mitochondrial respiratory chain-administration of antioxidants, and injection of healthy mitochondria. Exploring the oocyte's cellular and molecular responses, in particular that of the mitochondria, might lead to the development of new strategies to mitigate the effects of various stressors on fertility.
... In rabbits, Abdel-Khalek et al. (2016) showed that daily oral administration of doe rabbits with Coenzyme Q10 or L-Carnitine as antioxidants can improve quality of recovered embryos. In human, dietary supplementation with Coenzyme Q10 may improve embryo quality (Scott, 2013;Bentov et al., 2010). In mouse, in vivo administration of the antioxidant epigallocatechin gallate (EGCG) was found to improve embryo quality (Roth et al., 2008). ...
Article
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This study aimed to evaluate whether orally treatment of doe rabbits with green tea extract (GTE) can eliminate the negative effects of hyperthermia on embryonic development in vitro. A total of 24 mature NZW does was randomly allotted into three groups, 8 in each. The 1st group was control, while the 2nd and 3th groups were orally treated with 1 ml distilled water contained 200 and 400 mg GTE/kg LBW, respectively, for one month and naturally mated with proven bucks. Embryos were recovered from slaughtered doe oviducts at blastocyst stage 72 h post-mating by flushing and morphologically evaluated. Only normal embryos at blastocyst stage were in vitro cultured at 38.5 °C for 48 h (normal temperature, NT) or at 41.5°C (hyperthermia, HT) for 6 h then at 38.5 °C for 42 h in 5% CO2 and 95% humidity to develop to expanded and hatched blastocysts. Results showed that embryo recovery rate was not significantly affected by GTE. Embryos of does treated with both GTE levels were better (P<0.05) than control embryos. The GTE at 400 mg/kg showed the highest normality rates, hatched blastocyst proportion, and the lowest degenerated embryos. Formation rate of expanded and hatched blastocysts was higher (P<0.05) for embryos cultured in vitro at NT than at HT, while proportion of degenerated embryos showed an opposite trend. Effect of interaction between GTE treatment and thermal condition was significant on proportion of expanded, hatched and degenerated embryos (P<0.05), reflecting an increase in hatched embryos and decreasing degenerated embryos proportions by increasing GTE level at NT and HT, but GTE treatment showed the highest hatched and the lowest degenerated embryos proportions with level of 200 mg/kg at NT and with level of 400 mg/kg at HT. In conclusion, the negative effect of heat stress on embryonic development in vitro may be eliminated by GTE treatment of heat stressed does.
... In this aspect, mitochondrial metabolism of both the male and female germ cells exert a crucial role [2]. Mitochondrial nutrient supplementation is also reported to be effective in many cases [3]. ...
Article
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Background: L-carnitine (LC), and its acetylated form, acetyl L-carnitine (ALC), have immense functional capabilities to regulate the oxidative and metabolic status of the female reproductive system. The vulnerability of this system to free radicals demand for advanced strategies to combat them. For this purpose, the ‘quasi vitamins’ LC and ALC can be used either individually, or in combination with each other or with other antioxidants. Main body: This review (a) summarizes the effects of carnitines on female fertility along with the findings from various in vivo and in vitro studies involving human, animal and assisted reproductive technology, and (b) proposes their mechanism of actions in improving female fertility through their integrated actions on reducing cellular stress, maintaining hormonal balance and enhancing energy production. They reportedly aid β-oxidation in oocytes, maintain its cell membrane stability by acetylation of phospholipids and amphiphilic actions, prevent free radical-induced DNA damage and also stabilize acetyl Co-A/Co-A ratio for adequate acetyl storage as energy supply to maintain the robustness of reproductive cells. Conclusion: While both LC and ALC have their applications in improving female fertility, ALC is preferred for its better antioxidant properties and LC for amelioration of energy supply to the cells. These beneficial effects show great promise in its application as a treatment option for women facing infertility disorders.
... Use of co-enzyme Q10 did not significantly impact on the success of embryo transfers within our study. Studies have suggested that coenzyme Q10 supplementation has positive effects on oocyte quality by improving mitochondrial performance, scavenging free radicals and preventing oxidative damage (30)(31). Within an aged animal model, Ben-Meir et al. (32) demonstrated that coenzyme Q10 supplementation "delayed depletion of ovarian reserve, restored oocyte mitochondrial gene expression and improved mitochondrial activity". ...
Article
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Background Many adjuvant therapies are employed during IVF treatment in an attempt to improve outcomes. The objective of our study was to evaluate the impact of thirteen adjuvants (Intralipid, steroids, melatonin, coenzyme Q10, Filgrastim, testosterone, DHEA, growth hormone, antibiotics, hCG infusion, aspirin, enoxaparin/heparin and dopamine agonists) on the success of embryo transfers. Methods This is a retrospective cohort study of all embryo transfers between January 2010 and April 2015 from a multi-site IVF clinic. To ensure data independence, random number was applied to each included transfer and used to pick an individual transfer for each patient (n=13,372). Outcomes were clinical pregnancy, live birth and pregnancy loss. Univariate comparison with Chi square testing and logistic regression analysis were used. The level of significance was p<0.05. Results Steroid use was significantly associated with both reduced clinical pregnancy loss (aOR 0.39, CI 0.19–0.76) and improved live birth rates (aOR 1.40, CI 1.11–1.77). While aspirin was associated with improved live birth rates (aOR 1.48, CI 1.08–2.02), melatonin was linked with reduced rates (aOR 0.66, CI 0.45–0.96). Analyses for all other adjuvant therapies did not reach statistical significance after logistic regression. Conclusion Many of the interventions investigated in this study fail to significantly demonstrate any effects on the success of embryo transfers. Our analysis results show negative effects with the use of melatonin; however, use of aspirin or steroids demonstrated promising, potentially beneficial outcomes. Additional exploration is needed to guide evidence-based practice.
... Aging in human and mouse oocytes is associated with decreased function of the CoQ10 synthetic enzyme prenyl (decaprenyl) diphosphate synthase (Pdss2) [7]. CoQ10 can improve quality of oocytes from older females [7][8][9]. CoQ10 decreases are associated with spontaneous miscarriage in humans [10]. Thus, CoQ10 improves oocyte and embryo function in vivo and in vitro and under stress and aging, but the mechanisms improving oocyte quality are not fully understood. ...
Article
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Purpose: We tested whether mitochondrial electron transport chain electron carrier coenzyme Q10 (CoQ10) increases ATP during bovine IVM and increases %M2 oocytes, mitochondrial polarization/mass, and Oct4, and decreases pAMPK and oocyte death. Methods: Bovine oocytes were aspirated from ovaries and cultured in IVM media for 24 h with 0, 20, 40, or 60 μM CoQ10. Oocytes were assayed for ATP by luciferase-based luminescence. Oocyte micrographs were quantitated for Oct4, pAMPK (i.e., activity), polarization by JC1 staining, and mitochondrial mass by MitoTracker Green staining. Results: CoQ10 at 40 μM was optimal. Oocytes at 40 μM enabled 1.9-fold more ATP than 0 μM CoQ10. There was 4.3-fold less oocyte death, 1.7-fold more mitochondrial charge polarization, and 3.1-fold more mitochondrial mass at 40 μM than at 0 μM CoQ10. Increased ATP was associated with 2.2-fold lower AMPK thr172P activation and 2.1-fold higher nuclear Oct4 stemness/potency protein at 40 μM than at 0 μM CoQ10. CoQ10 is hydrophobic, and at all doses, 50% was lost from media into oil by ~ 12 h. Replenishing CoQ10 at 12 h did not significantly diminish dead oocytes. Conclusions: The data suggest that CoQ10 improves mitochondrial function in IVM where unwanted stress, higher AMPK activity, and Oct4 potency loss are induced.
... Dietary supplementation with CoQ10 can improve mitochondrial function in oocytes and developing embryos and may decrease the aneuploidy rate in human oocytes. [113] CoQ10 is a key enzyme in energy production and a major cellular antioxidant [114] that aids in the transport of electrons in the mitochondrial respiratory chain and is essential for the stability of complex III. [115] ALA is a coenzyme involved in mitochondrial metabolism. ...
... Dietary supplementation with CoQ10 can improve mitochondrial function in oocytes and developing embryos and may decrease the aneuploidy rate in human oocytes. [113] CoQ10 is a key enzyme in energy production and a major cellular antioxidant [114] that aids in the transport of electrons in the mitochondrial respiratory chain and is essential for the stability of complex III. [115] ALA is a coenzyme involved in mitochondrial metabolism. ...
Article
Full-text available
Fertility disorders have become a growing problem worldwide. It is well known that female fertility decreases with age, previous studies suggested that the age-related decline in female fertility potential was largely due to decrease in oocyte quality and mitochondrial dysfunction. Mitochondria play a crucial role during the process of oocyte maturation. Mitochondrial genetic, numerical and structural defects occur in oocyte aging process, mitochondrial abnormalities are believed to contribute to age-related infertility. Improvement of the mitochondrial function can lead to better fertility outcomes, and application of mitochondria replacement strategy or mitochondrial transfer to age-related infertility will be possible in the future. This review paper, we are trying to discuss current understanding about age-related changes in oocyte quality and mitochondrial dysfunction.
Article
The purpose of this experiment was to explore whether coenzyme Q10 (CoQ10) improves the quality of sheep semen stored at room temperature by attenuating oxidative stress. Semen was diluted without (control group), and with antioxidants (5, 50, 250, and 500 μmol/L CoQ10). Sperm kinetic parameters and plasma membrane integrity were determined, and the reactive oxygen species (ROS), malondialdehyde (MDA), adenosine triphosphate (ATP), mitochondrial membrane potential (MMP), total antioxidant capacity (TAOC), catalase (CAT), and superoxide dismutase (SOD) activity were evaluated on the fifth day of semen preservation. The results showed that compared with the control group, the progressive motility in the 50 μmol/L group was higher (p < 0.05) within 2–5 days, and the plasma membrane integrity of sperm was higher in the 50 μmol/L group. The ROS content in the 5 and 50 μmol/L groups was reduced. The MDA level was reduced in the CoQ10 supplementation groups (p < 0.05). Additionally, the CAT, SOD, TAOC, ATP and MMP levels in the 50 μmol/L group were higher than those in the control group (p < 0.05). In conclusion, CoQ10 improved the quality of ram semen by alleviating oxidative stress, and 50 μmol/L CoQ10 was the optimum concentration.
Article
Oocyte quality is one of the key factors affecting the outcome of ART. Therefore, how to improve oocyte quality has become an urgent problem in the field of ART. In this study we evaluated the effect of resveratrol (RSV), added during the process of superovulation, on embryonic development in mice. The results showed that the blastocyst rate was significantly higher in the RSV treated group than in the control group when oocytes were parthenogenetically activated in vitro (61.67 vs 41.51%, P = 0.032). In the naturally fertilized oocytes group, the rates of cleavage and blastocyst were significantly higher in the RSV treatment group than in the control group (74.47% vs 60.98%, P = 0.035; 96.19% vs 70.00%, P = 0.000, respectively). For the aged mice, the average number of oocytes, the rates of cleavage and blastocyst were also significantly higher in RSV treated groups than in the control group (19.47 ± 5.98 vs 10.30 ± 4.82, P = 0.028; 69.03 vs 50.75%, P = 0.014; 64.10% vs 44.12%, P = 0.049, respectively). Mitochondrial membrane potential and mtDNA copy number in oocytes were significantly increased after RSV treatment in both the young and aged populations. The expression of mitochondrial biogenesis related genes was significantly upregulated in cumulus cells of young and aged mice following RSV treatment. Our data suggest that supplementation of RSV during superovulation improves oocytes quality in young and aged mice, increases the number of oocytes retrieved from aged mice, and improves oocytes mitochondrial function.
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Objectives The alteration of bioenergetics by oocytes in response to the demands of various biological processes plays a critical role in maintaining normal cellular physiology. However, little is known about the association between energy sensing and energy production with energy-dependent cellular processes like meiosis. Materials and methods We demonstrated that cell cycle-dependent mitochondrial Ca²⁺ connects energy sensing to mitochondrial activity in meiosis progression within mouse oocytes. Further, we established a model in mouse oocytes using siRNA knockdowns that target mitochondrial calcium uniporters (MCUs) in order to inhibit mitochondrial Ca²⁺ concentrations. Results Decreased numbers of oocytes successfully progressed to the germinal vesicle stage and extruded the first polar body during in vitro culture after inhibition, while spindle checkpoint-dependent meiosis was also delayed. Mitochondrial Ca²⁺ levels changed, and this was followed by altered mitochondrial masses and ATP levels within oocytes during the entirety of meiosis progression. Abnormal mitochondrial Ca²⁺ concentrations in oocytes then hindered meiotic progress and activated AMP-activated protein kinase (AMPK) signalling that is associated with gene expression. Conclusions These data provide new insight into the protective role that MCU-dependent mitochondrial Ca²⁺ signalling plays in meiotic progress, in addition to demonstrating a new mechanism of mitochondrial energy regulation by AMPK signalling that influences meiotic maturation.
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Incorporation of Coenzyme Q10 (CoQ10) to the freezing medium provides advantageous effect for sperm cryopreservation in a variety of animal species, yet which has not been tested in giant grouper (Epinephelus lanceolatus). This research was designed to elucidate if CoQ10 could be used as a potential additive to improve giant grouper sperm quality after cryopreservation. After the process of freezing and thawing, various sperm quality parameters including motility, viability, apoptosis, mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS) generation, DNA fragmentation as well as fertilization rate were evaluated with CoQ10 added at concentrations of 0, 25, 50 and 100 μM. Compared to the control group (0 μm), addition of CoQ10 in the medium yielded significantly higher total motility and curvilinear velocity, whereas the progressive motility, straight-line velocity and average path velocity were not differ from each other. An obvious improvement in viability was observed in spermatozoa cryopreserved with 25 and 50 μM CoQ10, while the apoptosis rate in CoQ10 treated groups (25, 50 and 100 μM) exhibited significantly lower values than that of the control. Besides, the production of ROS was significantly decreased with CoQ10 addition groups when compared with the control. In consistent with the improvement in antioxidant defense, CoQ10 supplementation in the medium also enhanced mitochondrial activity and reduced DNA fragmentation. In addition, freezing medium supplemented with CoQ10 also improved the fertilization success, a significantly higher fertilization rate was recorded at the concentration of 50 μM, but this value was not differ from that of 25 μM. Overall, the antioxidant CoQ10 provided an obvious beneficial effect on post-thaw quality of giant grouper spermatozoa. It was concluded that the optimal concentration of CoQ10 is 50 μM in the freezing medium.
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As the vital organelles for cell energy metabolism, mitochondria are essential for oocyte maturation, fertilization, and embryo development. Abnormalities in quantity, quality, and function of mitochondria are closely related to poor fertility and disorders, such as decreased ovarian reserve (DOR), premature ovarian aging (POA), and ovarian aging, as well as maternal mitochondrial genetic disease caused by mitochondrial DNA (mtDNA) mutations or deletions. Mitochondria have begun to become a therapeutic target for infertility caused by factors such as poor oocyte quality, oocyte aging, and maternal mitochondrial genetic diseases. Mitochondrial replacement therapy (MRT) has attempted to use heterologous or autologous mitochondria to rebuild healthy state of oocyte by increasing the amount of mitochondria (e.g., partial ooplasm transfer, autologous mitochondrial transfer), or to stop the transmission of mtDNA diseases by replacing abnormal maternal mitochondria (e.g., pronuclei transfer, spindle transfer, polar body transfer). Among them, autologous mitochondrial transfer is the most promising therapeutic technology as of today which does not involve using a third party, but its clinical efficacy is controversial due to many factors such as the aging phenomenon of germ line cells, the authenticity of the existence of ovarian stem cells (OSC), and secondary damage caused by invasive surgery to patients with poor ovarian function. Therefore, the research of optimal autologous cell type that can be applied in autologous mitochondrial transfer is an area worthy of further exploration. Besides, the quality of germ cells can also be probably improved by the use of compounds that enhance mitochondrial activity (e.g., coenzyme Q10, resveratrol, melatonin), or by innovative gene editing technologies which have shown capability in reducing the risk of mtDNA diseases (e.g., CRISPR/Cas9, TALENTs). Though the current evidences from animal and clinical trials are not sufficient, and some solutions of technical problems are still needed, we believe this review will guide a new direction in the possible clinical applied mitochondrial-related therapeutic strategies in reproductive medicine.
Chapter
Coenzyme Q10 (CoQ10) intake and supplementation has been directly and indirectly associated with physiological function relative to exercise, aging and reproduction. This chapter describes several significant aspects regarding biochemical properties and mechanism of action of CoQ10 in male and female fertility and reproduction. This effect is mainly through its action as an antioxidant, protecting against oxidative stress by controlling the levels of reactive oxygen species (ROS) associated with reproductive pathologies. Although some studies support the evidence of use of CoQ10 to improve fertility, the available literature is contradictory and conflicting due to lack of standardization regarding type, dosage and time frame of treatment with CoQ10 as well as the bio-specimen, the exercise protocol employed and the assays used to analyze these specimens. However, CoQ10 supplementation seems to be able to improve both male and female gamete physiology, conception and embryo development and pregnancy success, something that may be related to the protecting effect against ROS-related fertility issues. It seems it may, as well, attenuate somewhat the negative impact of age on fertility, though discontinuation of treatment will result in cessation or diminution of such effect.
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Objective To evaluate the effect of coenzyme Q10 (CoQ10) supplementation on oocyte maturation rates and postmeiotic aneuploidy rates during in vitro maturation (IVM) of human oocytes. Design Clinical laboratory observation. Setting Hospital and university laboratories. Patient(s) Forty-five patients aged ≥38 years and 18 patients aged ≤30 years undergoing in vitro fertilization. Intervention(s) The germinal vesicle–stage oocytes and associated cumulus cells were cultured in IVM media for 24–48 hours with or without 50 μmol/L CoQ10. Oocyte maturation rates were determined based on the presence or absence of the first polar body. Postmeiotic aneuploidies were determined using next-generation sequencing analyses of biopsied polar bodies. Main Outcome Measure(s) Oocyte maturation rates, postmeiotic oocyte aneuploidy rates, and chromosome aneuploidy frequencies. Result(s) In women aged 38–46 years, 50 μmol/L CoQ10 significantly increased oocyte maturation rates (82.6% vs. 63.0%; P=.035), reduced oocyte aneuploidy rates (36.8% vs. 65.5%; P=.020), and reduced chromosome aneuploidy frequencies (4.1% vs. 7.0%; P=.012. In women aged ≤30 years, we failed to demonstrate an effect of CoQ10 on oocyte maturation rates or postmeiotic aneuploidies. Conclusion(s) CoQ10 supplementation during IVM increased oocyte maturation rates and reduced postmeiotic aneuploidies for older women.
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A now large body of work has solidified the central role that mitochondria play in oocyte development, fertilization, and embryogenesis. From these studies, a new technology termed autologous germline mitochondrial energy transfer was developed for improving pregnancy success rates in assisted reproduction. Unlike prior clinical studies that relied on the use of donor, or nonautologous, mitochondria for microinjection into eggs of women with a history of repeated in vitro fertilization failure to enhance pregnancy success, autologous germline mitochondrial energy transfer uses autologous mitochondria collected from oogonial stem cells of the same woman undergoing the fertility treatment. Initial trials of autologous germline mitochondrial energy transfer during - in vitro fertilization at three different sites with a total of 104 patients indicated a benefit of the procedure for improving pregnancy success rates, with the birth of children conceived through the inclusion of autologous germline mitochondrial energy transfer during in vitro fertilization. However, a fourth clinical study, consisting of 57 patients, failed to show a benefit of autologous germline mitochondrial energy transfer– in vitro fertilization versus in vitro fertilization alone for improving cumulative live birth rates. Complicating this area of work further, a recent mouse study, which claimed to test the long-term safety of autologous mitochondrial supplementation during in vitro fertilization, raised concerns over the use of the procedure for reproduction. However, autologous mitochondria were not actually used for preclinical testing in this mouse study. The unwarranted fears that this new study’s erroneous conclusions could cause in women who have become pregnant through the use of autologous germline mitochondrial energy transfer during- in vitro fertilization highlight the critical need for accurate reporting of preclinical work that has immediate bearing on human clinical studies.
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Mitochondrial dysfunction is strongly associated with the oocyte quality and aging, wherein the aged oocytes are related to the actin cytoskeleton integrity; however, whether this integrity is associated with mitochondrial dysfunction in oocytes from aged mice remains unclear. In the present study, we investigated the relationship between mitochondrial dysfunction and actin cytoskeleton instability in oocytes from the aged mice. We performed comparable analysis of mitochondrial motility between young, 1.5 μM cytochalasin B (CB)-treated young oocytes, and aged oocytes by confocal live imaging. Moreover, we analyzed the relationships between mitochondrial motility and maturation ratios, including ATP production ratio of the young, CB-treated young, and aged oocytes. Actin cytoskeleton instability in the aged oocytes and CB-treated young oocytes led to a significant decrease in the mitochondrial motility and low ATP productive ratios compared to those in the young group. Our data suggest that the actin cytoskeleton instability is presumably the primary cause for the loss of mitochondrial function in the aged murine oocytes.
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Background: Infertility is defined as failure in fertility after having sex for at least one year, if no contraceptive method is used, and 15% of the world's population is involved, of which 20-70 percent is related to men. Studies show that infertility is associated with a decrease in Q10 levels in the serum and seminal fluid, and its supplementation can reduce the symptoms of infertility, and improve it as well. Methods: The purpose of this study was to review the research done to investigate the relationship between Q10 and infertility. Clinical trial studies on the effect of supplementation of Q10 on male infertility from PubMed, Scopus, ISI, and Google Scholar databases between 2000 and 2017 were assessed using the keywords of coenzyme Q10, ubiquinol-10, infertility, male infertility, male fertility problems, semen parameters, sexual dysfunction. Findings: In most clinical trial studies, supplementation of Q10 had a positive effect on sperm parameters such as concentration, morphology, and movement. DNA fragmentation was also reduced; moreover, antioxidant enzymes of catalase and superoxide dismutase as well as total antioxidant capacity were significantly higher than before the intervention. However, some studies found no significant effect of Q10 on the sperm parameters. Conclusion: In most studies, the positive effects of Q10 supplement on sperm parameters, DNA damage, antioxidant capacity, and antioxidant enzymes have been proven, but due to the lack of studies, more clinical trial studies are needed in this area.
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Decline in successful conception decreases more rapidly after 38 years of age owing to follicular depletion and decreased oocyte quality. However, limited information is available regarding the underlying mechanism and the useful treatment. This study aimed to evaluate the effects of growth hormone supplementation on oocyte maturation in vivo in aged and young mice and to determine its effect on mitochondrial function. The influence of three different doses of recombinant human growth hormone (rhGH) (0.4 mg/kg/d, 0.8 mg/kg/d, and 1.6 mg/kg/d) for 8 weeks before ovarian stimulation was analyzed. Superovulated oocytes were released from the oviduct of Twelve-week-old (12W) and fourty-week-old (40W) female C57BL/6J mice 14-16 h after administration of human chorionic gonadotropin. Ovarian follicle and morphological analysis and oocyte maturation parameters were then evaluated. This study is the first, to our knowledge, to report that medium- and high-dose rhGH significantly increases antral follicles in aged mice but anti-Müllerian hormone (AMH) levels. Furthermore, derived oocytes, MII stage oocyte rate, adenosine triphosphate (ATP) levels, mitochondrial membrane potential and frequencies of homogeneous mitochondrial distribution increased. In contrast, in both aged and young mice, the mitochondrial DNA (mtDNA) copy numbers per oocyte were similar before rhGH administration, and upon saline administration, they did not differ significantly. We conclude that medium-dose rhGH supplementation before standard ovarian stimulation regimens improves oocyte quality in aged mice, probably by enhancing mitochondrial functionality.
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Maternal age has a significant effect on oocyte developmental competence. Overall, evidence suggests that oocytes from both prepubertal females and reproductively aged females are inherently less competent. Reduced oocyte quality in both age groups is problematic for human medicine and agriculture. Some of the cellular mechanisms implicated in poor oocyte quality associated with maternal age are mitochondrial function and location, reduction of oxygen radicals, balance of metabolic pathways, regulation of maternal mRNAs and appropriate communication between the oocyte and cumulus cells. However, additional knowledge must be gained about the deficiencies present in prepubertal and reproductively aged oocytes that result in poor developmental potential before significant improvement can be achieved. This review discusses the evidence currently available regarding oocyte quality at both ends of the maternal age spectrum, what we know, or hypothesise, about the mechanisms involved and current thoughts regarding potential treatment for improvement.
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The mitochondrial DNA (mtDNA) 'mutator' mouse, also called the 'POLG' mouse, is a well-characterized model frequently used for studies of progeroid aging. Harboring a mutation in the proofreading domain of the mitochondrial polymerase, polymerase-γ (POLG), POLG mice acquire mtDNA mutations at an accelerated rate. This results in premature mitochondrial dysfunction and a systemic aging phenotype. Previous work has demonstrated that the progeroid phenotype in POLG is attenuated following endurance exercise, the only reported intervention to extend healthspan and lifespan of these mice. Herein, oocyte quality was evaluated in sedentary and exercised POLG mice. In mice homozygous for the POLG mutation, litter size is dramatically reduced as compared to heterozygous POLG mice. Following ovarian hyper-stimulation, oocytes were retrieved until 9 months of age in exercised and sedentary groups, with no oocytes ovulated thereafter. Although ovulated oocyte numbers were not impacted by exercise, we did find a modest improvement in both the ovarian follicle reserve and in oocyte quality based on meiotic spindle assembly, chromosomal segregation and mitochondrial distribution at 7 months of age in exercised POLG mice as compared to sedentary counterparts. Of note, analysis of mtDNA mutational load revealed no differences between exercised and sedentary groups. Collectively, these data indicate that exercise differentially impacts somatic tissues of the POLG mouse as compared to oocytes, highlighting important mechanistic differences between mitochondrial regulatory mechanisms in the soma and the germline.
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Germinal vesicle transplantation (GVT) has been proposed as a possible treatment to correct age-related oocyte aneuploidy caused by dysfunctional ooplasm. How healthy ooplasm regu-lates normal meiosis and subsequent development has yet to be elucidated, but impaired mitochondrial metabolism may be at-tributable to incomplete segregation of the oocyte chromo-somes. In the present study, after ooplasmic mitochondrial dam-age by photoirradiating chloromethyl-X-rosamine, examination of the oocyte nuclei's ability to survive after transfer into healthy ooplasts was performed. To assess their fertilizability and poten-tial for development, GVT oocytes were fertilized by intracyto-plasmic sperm injection (ICSI) and transferred to foster mice. Condition of the offspring at birth was assessed, and epigenetic analysis was performed. Photosensitization consistently inhibit-ed oocyte maturation. However, after GVT of photosensitized nuclei into healthy ooplasts, 67.2% were reconstituted, and 76.2% of these matured normally, with an overall rate of 51.2%, much higher than that (6.0%) in the mitochondrially injured oocytes. After ICSI, 65.8% (52/79) of GVT oocytes were fertilized normally, and 21.1% (11/52) eventually reached the blastocyst stage. The transfer of 132 two-cell GVT embryos into the oviducts of pseudopregnant females resulted in 17 appar-ently healthy live offspring. For some key developmental genes, a high level of expression was identified in the GVT and ''res-cue''-derived fetal adnexa. Thus, one can induce in oocyte mi-tochondria a photosensitization-based type of damage, which consistently inhibits GV breakdown, meiotic spindle formation, chromosomal segregation, and polar body extrusion. Germinal vesicle transplanted and rescued oocytes were able to undergo maturation, fertilization, and embryonic cleavage and, ultimate-ly, to develop to term. This approach may provide a model with which to study the age-related ooplasmic dysfunction seen in human oocytes. fertilization, gamete biology, gene regulation, genomic imprint-ing, germinal vesicle transplantation, meiosis, mitochondrial pho-tosensitization, oocyte development, ooplasmic dysfunction
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Ooplasmic transfer from fertile donor oocytes into potentially compromised recipient patient oocytes has led to the birth of nearly 30 babies worldwide. Cytoplasmic transplantation has caused apprehension, since the mixing of human ooplasm from two different maternal sources may generate mitochondrial (mt) heteroplasmy (both recipient and donor mtDNA) in offspring. This investigation traced the mitochondrial donor population both during the ooplasmic transfer technique and in the bloods of two 1 year old children using mtDNA fingerprinting. Donor ooplasm stained for active mitochondria was transferred into recipient ooplasm and the mitochondria were visualized by confocal microscopy after the microinjection procedure and fertilization. Heteroplasmy was found in the blood from each of the children. This report is the first case of human germline genetic modification resulting in normal healthy children.
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Coenzyme Q (Q) is an essential component of the mitochondrial respiratory chain in eukaryotic cells but also is present in other cellular membranes where it acts as an antioxidant. Because Q synthesis machinery in Saccharomyces cerevisiae is located in the mitochondria, the intracellular distribution of Q indicates the existence of intracellular Q transport. In this study, the uptake of exogenous Q(6) by yeast and its transport from the plasma membrane to mitochondria was assessed in both wild-type and in Q-less coq7 mutants derived from four distinct laboratory yeast strains. Q(6) supplementation of medium containing ethanol, a non-fermentable carbon source, rescued growth in only two of the four coq7 mutant strains. Following culture in medium containing dextrose, the added Q(6) was detected in the plasma membrane of each of four coq7 mutants tested. This detection of Q(6) in the plasma membrane was corroborated by measuring ascorbate stabilization activity, as catalyzed by NADH-ascorbate free radical reductase, a transmembrane redox activity that provides a functional assay of plasma membrane Q(6). These assays indicate that each of the four coq7 mutant strains assimilate exogenous Q(6) into the plasma membrane. The two coq7 mutant strains rescued by Q(6) supplementation for growth on ethanol contained mitochondrial Q(6) levels similar to wild type. However, the content of Q(6) in mitochondria from the non-rescued strains was only 35 and 8%, respectively, of that present in the corresponding wild-type parental strains. In yeast strains rescued by exogenous Q(6), succinate-cytochrome c reductase activity was partially restored, whereas non-rescued strains contained very low levels of activity. There was a strong correlation between mitochondrial Q(6) content, succinate-cytochrome c reductase activity, and steady state levels of the cytochrome c(1) polypeptide. These studies show that transport of extracellular Q(6) to the mitochondria operates in yeast but is strain-dependent. When Q biosynthesis is disrupted in yeast strains with defects in the intracellular transport of exogenous Q, the bc(1) complex is unstable. These results indicate that delivery of exogenous Q(6) to mitochondria is required fore activity and stability of the bc(1) complex in yeast coq mutants.
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Mitochondria are organelles responsible for oxidative phosphorylation, the main energy source for all eukaryotic cells. In oocytes and embryos, it seems that mitochondria provide sufficient energy for fecundation by supporting spindle formation during meiosis II, and for implantation. Since mitochondria are inherited from mother to child, it is important that oocyte mitochondria should be intact. Older women seem to have more mitochondrial DNA mutations, which can be responsible for poor implantation and aneuploidy, two conditions that occur more often in this group. In the present report we propose a new model to explain why older women have poor implantation rates.
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Germinal vesicle transplantation (GVT) has been proposed as a possible treatment to correct age-related oocyte aneuploidy caused by dysfunctional ooplasm. How healthy ooplasm regulates normal meiosis and subsequent development has yet to be elucidated, but impaired mitochondrial metabolism may be attributable to incomplete segregation of the oocyte chromosomes. In the present study, after ooplasmic mitochondrial damage by photoirradiating chloromethyl-X-rosamine, examination of the oocyte nuclei's ability to survive after transfer into healthy ooplasts was performed. To assess their fertilizability and potential for development, GVT oocytes were fertilized by intracytoplasmic sperm injection (ICSI) and transferred to foster mice. Condition of the offspring at birth was assessed, and epigenetic analysis was performed. Photosensitization consistently inhibited oocyte maturation. However, after GVT of photosensitized nuclei into healthy ooplasts, 67.2% were reconstituted, and 76.2% of these matured normally, with an overall rate of 51.2%, much higher than that (6.0%) in the mitochondrially injured oocytes. After ICSI, 65.8% (52/79) of GVT oocytes were fertilized normally, and 21.1% (11/52) eventually reached the blastocyst stage. The transfer of 132 two-cell GVT embryos into the oviducts of pseudopregnant females resulted in 17 apparently healthy live offspring. For some key developmental genes, a high level of expression was identified in the GVT and "rescue"-derived fetal adnexa. Thus, one can induce in oocyte mitochondria a photosensitization-based type of damage, which consistently inhibits GV breakdown, meiotic spindle formation, chromosomal segregation, and polar body extrusion. Germinal vesicle transplanted and rescued oocytes were able to undergo maturation, fertilization, and embryonic cleavage and, ultimately, to develop to term. This approach may provide a model with which to study the age-related ooplasmic dysfunction seen in human oocytes.
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Coenzyme Q10 (CoQ10) is a naturally occurring component present in living cells. Its physiological function is to act as an essential cofactor for ATP production, and to perform important antioxidant activities in the body. In most countries, CoQ10 has been widely used as a dietary supplement for more than 20 years. Recently, the use of CoQ10 as a dietary supplement has grown with a corresponding increase in daily dosage. The present review describes the safety profile of CoQ10 on the basis of animal and human data. The published reports concerning safety studies indicate that CoQ10 has low toxicity and does not induce serious adverse effects in humans. The acceptable daily intake (ADI) is 12mg/kg/day, calculated from the no-observed-adverse-effect level (NOAEL) of 1200 mg/kg/day derived from a 52-week chronic toxicity study in rats, i.e., 720 mg/day for a person weighing 60 kg. Risk assessment for CoQ10 based on various clinical trial data indicates that the observed safety level (OSL) for CoQ10 is 1200 mg/day/person. Evidence from pharmacokinetic studies suggest that exogenous CoQ10 does not influence the biosynthesis of endogenous CoQ9/CoQ10 nor does it accumulate into plasma or tissues after cessation of supplementation. Overall, these data from preclinical and clinical studies indicate that CoQ10 is highly safe for use as a dietary supplement. Additionally, analysis of CoQ10 bioavailability or its pharmacokinetics provides the pertinent safety evaluation for CoQ10.
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Patients with CHF, NYHA class IV, often fail to achieve adequate plasma CoQ10 levels on supplemental ubiquinone at dosages up to 900 mg/day. These patients often have plasma total CoQ10 levels of less than 2.5 microg/ml and have limited clinical improvement. It is postulated that the intestinal edema in these critically ill patients may impair CoQ10 absorption. We identified seven patients with advanced CHF (mean EF 22%) with sub-therapeutic plasma CoQ10 levels with mean level of 1.6 microg/ml on an average dose of 450 mg of ubiquinone daily (150-600 mg/day). All seven of these patients were changed to an average of 580 mg/day of ubiquinol (450-900 mg/day) with follow-up plasma CoQ10 levels, clinical status, and EF measurements by echocardiography. Mean plasma CoQ10 levels increased from 1.6 microg/ml (0.9-2.0 microg/ml) up to 6.5 microg/ml (2.6-9.3 microg/ml). Mean EF improved from 22% (10-35%) up to 39% (10-60%) and clinical improvement has been remarkable with NYHA class improving from a mean of IV to a mean of II (I to III). Ubiquinol has dramatically improved absorption in patients with severe heart failure and the improvement in plasma CoQ10 levels is correlated with both clinical improvement and improvement in measurement of left ventricular function.
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Uptake of dietary coenzyme Q (CoQ) into organs is limited but there are some exceptions such as adrenal glands and ovaries. Under deficient conditions an optimal solution could be stimulation of the endogenous synthesis. In rodent exercise, cold exposure and a few substances elevate the CoQ levels to some extent. Investigations of the nuclear receptors PPARalpha, RXRalpha and LXRalpha&beta did not answer the question which nuclear receptor regulates CoQ biosynthesis and at present we cannot design a ligand for upregulation of the synthesis. Upon ultraviolet irradiation of CoQ a number of products are formed which influence the synthesis of the mevalonate pathway lipids. Among them epoxidated derivatives were identified. Upon chemical epoxidation of a series of polyisoprenoids it was found that none of the tested poly-cis polyisoprenols had any effect but some of the all-trans polyisoprenols stimulated CoQ synthesis and in some cases also inhibited cholesterol biosynthesis. Tocotrienol epoxides were proved to be very efficient, those having one epoxide in the side chain doubled or trebled the CoQ synthesis while those with two epoxides additionally also inhibited cholesterol synthesis by 50-90%. The elevation of CoQ synthesis was elicited by increased mRNA levels for biosynthetic enzymes while the inhibition point in the cholesterol synthesis was localized to oxidosqualene cyclase.
Article
Mitochondrial nucleoids (mt-nucleoids) of the A2780 line of cultured human cells were stained with DAPI and observed using an epifluorescence microscope. The mt-nucleoids appeared to be organized compactly in mitochondria. Numbers of mt-nucleoids per mitochondrion ranged from 1 to more than 10, and 70% were "multinucleated" mitochondria. Intensities of fluorescence of mt-nucleoids in each mitochondrion were measured by a video-intensified microscope system (VIM system) and copy numbers of mitochondrial DNA (mtDNA) in each mitochondria were determined. The copy numbers of mtDNA per mitochondrion ranged from 1 to 15, and the average was 4.6. Because the cells had 107 mitochondria on average, the copy number of mtDNA per cell was estimated to be about 500.
Article
Although the embryos of certain mammals, including man, can be cultured in vitro through several cleavage divisions1,2, it is only in the mouse that complete development through the preimplantation period (one-cell to the blastocyst stage3) occurs without affecting subsequent embryonic viability after transfer1,4. But even in the mouse, development in vitro from the one-cell to the blastocyst stage is restricted to certain inbred strains and F1 hybrids1,3,5,6. In most randomly bred strains the one-cell embryo becomes blocked at the two-cell stage in vitro and it will only continue development if transferred back into the oviduct7. Here we present evidence that this so-called `in vitro two-cell block' can be obviated by injecting small amounts of cytoplasm from embryos which do not exhibit this block.
Article
CoQ10 is intrinsic to human tissues and is a vitamin, according to the basic science of nutrition. It is known that CoQ10, plays a role in the respiratory process, moreover it seems to be involved in the mechanism of blood coagulation. As a vitamin a deficiency of CoQ10 may be related to some disease, that is, first of all, a disease is bioenergetics. It has been demonstrated that during aging, other than a diminution of EFA (and an increase of palmitoleic and eicosatrienoic fatty acids), a decrease of about the 20-30% in the heart CoQ10 levels occurs in the rat. Perhaps these modifications may be intrinsic to the "biochemical" changes of aging.
Article
To determine whether oocytes from women harbor deletions in mitochondrial DNA (mtDNA) and whether deleted mtDNA is more common in oocytes from older women than oocytes from younger women. A polymerase chain reaction (PCR)-based strategy, which depends on deletions approximating otherwise widely separated primers to demonstrate mtDNA deletions in individual oocytes, was used. Yale In Vitro Fertilization Clinic and Laboratory at Yale University School of Medicine. Primers flanked a region of the mitochondrial genome in which long direct repeated sequence predispose to deletions. The primers identified the 0.5-kb "common" deletion. Deleted mtDNA was represented by a 0.5-kb band when primers separated by 5 kb were used. Control reactions used primers that amplify mtDNA outside the deletion hotspot. Positive controls included brain and/or muscle from aged individuals, and negative controls included fetal tissue and DNA-free blanks. Nested primers confirmed the specificity of the deleted product. Unfertilized oocytes, muscle, and brain tissue contained PCR products consistent with deleted mtDNA. Fetal tissue lacked the mtDNA deletion product. Deleted mtDNA was detected in single oocytes. Oocytes from older women were more likely to contain deleted mtDNA than oocytes from younger women. Deleted mtDNA in unfertilized oocytes may serve as a marker of oocyte senescence.
Article
Using quantitative PCR, we have determined that a human oocyte contains approximately 100,000 mitochondrial genomes (mtDNAs). We have also found that some oocytes harbor measurable levels (up to 0.1%) of the so-called common deletion, an mtDNA molecule containing a 4,977-bp rearrangement that is present in high amounts in many patients with "sporadic" Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia (PEO). This is the first demonstration that rearranged mtDNAs are present in human oocytes, and it provides experimental support for the supposition that pathogenic deletions associated with the ontogeny of sporadic KSS and PEO can be transmitted in the female germ line, from mother to child. The relevance of these finding to the accumulation of extremely low levels of deleted mtDNAs in both somatic and germ-line tissues during normal human aging is also discussed.
Article
This study aims at determining a cutoff value differentiating the fetal from the adult coenzyme Q10 (CoQ10) values and comparing substantial increases in CoQ10 plasma levels in fetuses with hypoxic hypoxia and nonimmune fetal hydrops. We have selected 61 pregnancies and determined the CoQ10 levels in fetal and maternal samples obtained by cordocentesis. Our study included a control group and pregnancies with intrauterine growth retardation, Rh isoimmunization, nonimmune fetal hydrops, and fetal malformations. To differentiate the fetal from the adult values we have set 0.3 mg/ml as the cutoff value. The CoQ10 were higher only in fetuses with hypoxic hypoxia and nonimmune hydrops. Normal fetal CoQ10 plasma levels are lower than 0.3 mg/ml.
Article
Molecular geneticists and ovarian physiologists today face the challenge of defining and reconciling two major biological imperatives that each center on oogenesis, folliculogenesis and competition between ovarian follicles: (1), defining how the mitochondrial genome--important in both aging and a number of serious mitochondrial diseases--is refreshed and purified as it passes, via the oocyte's cytoplasm, from one generation to the next; and (2), endeavouring to discover what cytoplasmic factor(s) it is that permits some eggs but not others to produce viable embryos and ongoing pregnancies. We review here in detail the passage of mitochondria through the female germ cell line. For mitochondria, the processes of oogenesis, follicle formation and loss constitute a restriction/amplification/constraint event of the kind predicted by L. Chao for purification and refinement of a haploid genome. We argue that maintaining the integrity of mitochondrial inheritance is such a strong evolutionary imperative that we should expect at least some features of ovarian follicular formation, function and loss to be primarily adapted to this specific purpose. We predict, moreover, that to prevent accumulation of mild mitochondrial genomes in the population there is a need for physiological female sterility prior to total depletion of ovarian oocytes, a phenomenon for which there is empirical evidence and which we term the oöpause.
Article
Along with the transition from maternal to embryonic genome control the mammalian preimplantation embryo undergoes significant changes in its physiology during development. Concomitant with these changes are altering patterns of nutrient uptake and differences in the subsequent fate of such nutrients. The most significant nutrients to the developing mammalian preimplantation embryo are carbohydrates and amino acids, which serve not only to provide energy but also to maintain embryo function by preventing cellular stress induced by suboptimal culture conditions in vitro. It is subsequently proposed that optimal development of the mammalian embryo in culture requires the use of two or more media, each designed to cater for the changing requirements of the embryo. Importantly, culture conditions that maintain the early embryo are not ideal for the embryo post-compaction, and conditions that support excellent development and differentiation of the blastocyst can actually be inhibitory to the zygote. A marker of in vitro-induced cellular stress to the embryo is the relative activity of the metabolic pathways used to generate energy for development. Quantification of embryo energy metabolism may therefore serve as a valuable marker of embryo development and viability.
Article
The strictly maternal inheritance of mitochondria and mitochondrial DNA (mtDNA) in mammals is a developmental paradox promoted by an unknown mechanism responsible for the destruction of the sperm mitochondria shortly after fertilization. We have recently reported that the sperm mitochondria are ubiquitinated inside the oocyte cytoplasm and later subjected to proteolysis during preimplantation development (P. Sutovsky et al., Nature 1999; 402:371-372). Here, we provide further evidence for this process by showing that the proteolytic destruction of bull sperm mitochondria inside cow egg cytoplasm depends upon the activity of the universal proteolytic marker, ubiquitin, and the lysosomal apparatus of the egg. Binding of ubiquitin to sperm mitochondria was visualized by monospecific antibodies throughout pronuclear development and during the first embryonic divisions. The recognition and disposal of the ubiquitinated sperm mitochondria was prevented by the microinjection of anti-ubiquitin antibodies and by the treatment of the fertilized zygotes with lysosomotropic agent ammonium chloride. The postfecundal ubiquitination of sperm mitochondria and their destruction was not seen in the hybrid embryos created using cow eggs and sperm of wild cattle, gaur, thus supporting the hypothesis that sperm mitochondrion destruction is species specific. The initial ligation of ubiquitin molecules to sperm mitochondrial membrane proteins, one of which could be prohibitin, occurs during spermatogenesis. Even though the ubiquitin cross-reactivity was transiently lost from the sperm mitochondria during epididymal passage, likely as a result of disulfide bond cross-linking, it was restored and amplified after fertilization. Ubiquitination therefore may represent a mechanism for the elimination of paternal mitochondria during fertilization. Our data have important implications for anthropology, treatment of mitochondrial disorders, and for the new methods of assisted procreation, such as cloning, oocyte cytoplasm donation, and intracytoplasmic sperm injection.
Article
To test the hypothesis that mitochondrial DNA (mtDNA) deletions are more prevalent in granulosa cells from women of advanced reproductive age than from younger women undergoing IVF. Granulosa cells screened for presence or absence of the 4977-bp deletion in human mtDNA. University-based fertility clinic. Twenty-four women divided equally between two groups: </=34 years old and >/=38 years old. Patients were given gonadotropin stimulation in preparation for IVF with granulosa cells isolated at the time of follicular aspiration. Presence or absence of the 4977-bp deletion in human mtDNA. Seven out of 12 women analyzed who were <38 years old and 0 out of 12 women who were >38 years old had normal mtDNA as indicated by the presence of the 4977-bp fragment. These data suggest that women over the age of 38 have granulosa cells that contain a substantial decrease in the level of normal mitochondria as compared with women </=34 years.
Article
To determine the relationship between the intrinsic mitochondrial deltapsi of human embryos and the embryo karyotype. Analysis of mitochondrial deltapsi of living embryos followed by chromosomal enumeration with fluorescence in situ hybridization. A tertiary center for assisted reproduction technology. Fifty-two patients attending the fertility center for assisted reproduction. Donated embryos were loaded with a mitochondrial deltapsi-sensitive fluorescence dye. Mitochondrial deltapsi was measured by confocal microscopy. Subsequently, embryos were fixed and fluorescence in situ hybridization analysis was used to denote embryo karyotype. Mitochondrial deltapsi and embryo karyotype. An association was observed between low mitochondrial deltapsi and the detection of chaotic mosaicism. Analysis of oocytes suggested that this was due to the effect of low mitochondrial deltapsi on the morphology of the meiotic apparatus. The data suggest that the intrinsic mitochondrial deltapsi of human oocytes programs the developmental fate of embryos through an effect on the ability of oocytes to form a normal meiotic apparatus and not through nondisjunction.
Article
Mitochondria are cellular organelles regulating metabolism and cell death pathways. This study examined changes in mitochondrial membrane potential (deltapsim) throughout the stages of preimplantation development in mouse embryos conceived either in vivo or in vitro and human embryos donated to research from IVF. Embryos stained with the deltapsim-sensitive dye (JC-1) were quantified for the ratio of high- to low-polarized mitochondria using a deconvolution microscope. Overall, mouse zygotes and early embryos contain a subset of high-polarized mitochondria with a progressive increase in the ratio of deltapsim observed with increasing cleavage. A transient increase in the ratio of high to low deltapsim was observed in in vivo fertilized 2-cell stage embryos, coincident with embryonic genome activation in the mouse, but not in 2-cell embryos obtained through IVF. We further observed that arrested mouse 2-cell embryos possessed an increased ratio of deltapsim compared with non-arrested embryos. In human 8-cell embryos we observed an increased ratio of high- to low-polarized mitochondria with increasing degrees of embryo fragmentation. We concluded that the pattern of mitochondrial membrane potential progressively changes throughout preimplantation development, and that an aberrant shift in deltapsim could contribute to, or is associated with, decreased developmental potential.
Article
To clarify a potential therapeutic role of coenzyme Q(10) (CoQ(10)) in infertile men with idiopathic asthenozoospermia. Open, uncontrolled pilot study. Infertile men with idiopathic asthenozoospermia. CoQ(10) was administered orally; semen samples were collected at baseline and after 6 months of therapy. MAIN OUTCOME MEASURE (S): Semen kinetic parameters, including computer-assisted sperm data and CoQ(10) and phosphatidylcholine levels. CoQ(10) levels increased significantly in seminal plasma and in sperm cells after treatment. Phosphatidylcholine levels also increased. A significant increase was also found in sperm cell motility as confirmed by computer-assisted analysis. A positive dependence (using the Cramer's index of association) was evident among the relative variations, baseline and after treatment, of seminal plasma or intracellular CoQ(10) content and computer-determined kinetic parameters. The exogenous administration of CoQ(10) may play a positive role in the treatment of asthenozoospermia. This is probably the result of its role in mitochondrial bioenergetics and its antioxidant properties.
Article
Several lines of evidence suggest an impairment of mitochondrial function in the brain of patients with Parkinson's disease (PD). However, the presence of a detectable mitochondrial defect in extracerebral tissue of these patients remains a matter of dispute. Therefore, we investigated mitochondrial function in fibroblasts of 18 PD patients applying biochemical micromethods. Putative beneficial effects of coenzyme Q(10) (CoQ(10)), a potent antioxidant, on the mitochondrial function of skin fibroblast cultures were evaluated. Applying inhibitor titrations of the mitochondrial respiration to calculate flux control coefficients of respiratory chain complexes I and IV, we observed deficiencies of both complexes in cultivated skin fibroblasts of PD patients. Cultivation of fibroblasts in the presence of 5 microM CoQ(10) restored the activity of impaired respiratory chain complexes in the fibroblast cultures of 9 out of 18 PD patients. Our data support the presence of a generalised mitochondrial defect in at least a subgroup of patients with PD that can be partially ameliorated in vitro by coenzyme Q(10) treatment.