Biallelic variants in and cause deafness and (ovario)leukodystrophy.
van der Knaap Marjo S,Bugiani Marianna,Mendes Marisa I,Riley Lisa G,Smith Desiree E C,Rudinger-Thirion Joëlle,Frugier Magali,Breur Marjolein,Crawford Joanna,van Gaalen Judith,Schouten Meyke,Willems Marjolaine,Waisfisz Quinten,Mau-Them Frederic Tran,Rodenburg Richard J,Taft Ryan J,Keren Boris,Christodoulou John,Depienne Christel,Simons Cas,Salomons Gajja S,Mochel Fanny
OBJECTIVE:To describe the leukodystrophy caused by pathogenic variants in and , encoding mitochondrial leucyl transfer RNA (tRNA) synthase and mitochondrial and cytoplasmic lysyl tRNA synthase, respectively. METHODS:We composed a group of 5 patients with leukodystrophy, in whom whole-genome or whole-exome sequencing revealed pathogenic variants in or . Clinical information, brain MRIs, and postmortem brain autopsy data were collected. We assessed aminoacylation activities of purified mutant recombinant mitochondrial leucyl tRNA synthase and performed aminoacylation assays on patients' lymphoblasts and fibroblasts. RESULTS:Patients had a combination of early-onset deafness and later-onset neurologic deterioration caused by progressive brain white matter abnormalities on MRI. Female patients with pathogenic variants had premature ovarian failure. In 2 patients, MRI showed additional signs of early-onset vascular abnormalities. In 2 other patients with and pathogenic variants, magnetic resonance spectroscopy revealed elevated white matter lactate, suggesting mitochondrial disease. Pathology in one patient with pathogenic variants displayed evidence of primary disease of oligodendrocytes and astrocytes with lack of myelin and deficient astrogliosis. Aminoacylation activities of purified recombinant mutant leucyl tRNA synthase showed a 3-fold loss of catalytic efficiency. Aminoacylation assays on patients' lymphoblasts and fibroblasts showed about 50% reduction of enzyme activity. CONCLUSION:This study adds and pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. We discuss the specific MRI characteristics shared by leukodystrophies caused by mitochondrial tRNA synthase defects. We propose to add aminoacylation assays as biochemical diagnostic tools for leukodystrophies.
The protective role of melatonin in porcine oocyte meiotic failure caused by the exposure to benzo(a)pyrene.
Miao Yilong,Zhou Changyin,Bai Qingyun,Cui Zhaokang,ShiYang Xiayan,Lu Yajuan,Zhang Mianqun,Dai Xiaoxin,Xiong Bo
Human reproduction (Oxford, England)
STUDY QUESTION:Does melatonin restore the benzo(a)pyrene (BaP)-induced meiotic failure in porcine oocytes? SUMMARY ANSWER:Melatonin effectively inhibits the increased reactive oxygen species (ROS) level and apoptotic rate in BaP-exposed porcine oocytes to recover the meiotic failure. WHAT IS KNOWN ALREADY:BaP, a widespread environmental carcinogen found in particulate matter, 2.5 µm or less (PM2.5), has been shown to have toxicity at the level of the reproductive systems. BaP exposure disrupts the steroid balance, alters the expression of ovarian estrogen receptor and causes premature ovarian failure through the rapid depletion of the primordial follicle pool. In addition, acute exposure to BaP has transient adverse effects on the follicle growth, ovulation and formation of corpora lutea, which results in transient infertility. STUDY DESIGN, SIZE, DURATION:Porcine oocytes were randomly assigned to control, BaP-exposed and melatonin-supplemented groups. BaP was dissolved in dimethylsulphoxide and diluted to a final concentration of 50, 100 or 250 μM with maturation medium, respectively. Melatonin was dissolved in the absolute ethanol and diluted with maturation medium to a final concentration of 1 nM, 100 nM, 10 μM and 1 mM, respectively. The in vitro cultured oocytes from each group after treatment were applied to the subsequent analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS:Acquisition of oocyte meiotic competence was assessed using immunostaining, fluorescent intensity quantification and/or immunoblotting to analyse the cytoskeleton assembly, mitochondrial integrity, cortical granule dynamics, ovastacin distribution, ROS level and apoptotic rate. Fertilization ability of oocytes was examined by sperm binding assay and IVF. MAIN RESULTS AND THE ROLE OF CHANCE:BaP exposure resulted in the oocyte meiotic failure (P = 0.001) via impairing the meiotic apparatus, showing a prominently defective spindle assembly (P = 0.003), actin dynamics (P < 0.001) and mitochondrion integrity (P < 0.001). In addition, BaP exposure caused the abnormal distribution of cortical granules (P < 0.001) and ovastacin (P = 0.003), which were consistent with the observation that fewer sperm bound to the zona pellucida surrounding the unfertilized BaP-exposed eggs (P < 0.001), contributing to the fertilization failure (P < 0.001). Conversely, melatonin supplementation recovered, at least partially, all the meiotic defects caused by BaP exposure through inhibiting the rise in ROS level (P = 0.015) and apoptotic rate (P = 0.001). LIMITATIONS, REASONS FOR CAUTION:We investigated the negative impact of BaP on the oocyte meiotic maturation in vitro, but not in vivo. WIDER IMPLICATIONS OF THE FINDINGS:Our findings not only deeply clarify the potential mechanisms of BaP-induced oocyte meiotic failure, but also extend the understanding about how environmental pollutants influence the reproductive systems in humans. STUDY FUNDING/COMPETING INTERESTS:This study was supported by the National Natural Science Foundation of China (31571545) and the Natural Science Foundation of Jiangsu Province (BK20150677). The authors have no conflict of interest to disclose.
Transcripts encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles.
Ernst E H,Lykke-Hartmann K
Journal of assisted reproduction and genetics
PURPOSE:To study the presence and distribution of genes encoding free radical scavengers in human granulosa cells from primordial and primary ovarian follicles. METHODS:A class comparison study on existing granulosa cell transcriptome from primordial (n = 539 follicles) and primary (n = 261) follicles donated by three women having ovarian tissue cryopreserved before chemotherapy was performed and interrogated. RESULTS:In granulosa cells from primordial follicles, 30 genes were annotated 'mitochondrial dysfunction' including transcripts (PRDX5, TXN2) encoding enzymatic free radical scavengers peroxiredoxin 5 and thioredoxin 2. Several apoptosis regulation genes were noted (BCL2, CAS8, CAS9, AIFM1). In granulosa cells from primary follicles, mitochondrial dysfunction signalling pathway was annotated. High expression of transcripts encoding the free radical scavenger peroxiredoxin 3, as well as anti-apoptotic enzyme BCL2, was found. Interestingly, PARK7 encoding the deglycase (DJ-1) protein was expressed in granulosa cells from primary follicles. DJ-1 is implicated in oxidative defence and functions as a positive regulator of the androgen receptor and as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/serine-threonine protein kinase (AKT) signalling pathway suppressor PTEN. CONCLUSIONS:The results indicate extensive energy production and free radical scavenging in the granulosa cells of primordial follicles with potential implications for ovarian ageing, cigarette smoking, premature ovarian failure and polycystic ovarian syndrome. Furthermore, DJ-1 may be involved in androgen responsiveness and the regulation of follicle growth via PI3K/PTEN/AKT signalling pathway regulation in the granulosa cells of primary follicles. The involvement of mitochondrial free radical production in the age-related decline of competent oocytes is becoming apparent.
Melatonin as Potential Targets for Delaying Ovarian Aging.
Yang Yanzhou,Cheung Hoi-Hung,Zhang Cheng,Wu Ji,Chan Wai-Yee
Current drug targets
In previous studies, oxidative stress damage has been solely considered to be the mechanism of ovarian aging, and several antioxidants have been used to delay ovarian aging. But recently, more reports have found that endoplasmic reticulum stress, autophagy, sirtuins, mitochondrial dysfunction, telomeres, gene mutation, premature ovarian failure, and polycystic ovary syndrome are all closely related to ovarian aging, and these factors all interact with oxidative stress. These novel insights on ovarian aging are summarized in this review. Furthermore, as a pleiotropic molecule, melatonin is an important antioxidant and used as drugs for several diseases treatment. Melatonin regulates not only oxidative stress, but also the various molecules, and normal and pathological processes interact with ovarian functions and aging. Hence, the mechanism of ovarian aging and the extensive role of melatonin in the ovarian aging process are described herein. This systematic review supply new insights into ovarian aging and the use of melatonin to delay its onset, further supply a novel drug of melatonin for ovarian aging treatment.
Evaluation of mitochondria in oocytes following γ-irradiation.
Wang Qiaochu,Stringer Jessica M,Liu Jun,Hutt Karla J
Standard cytotoxic cancer treatments, such as radiation, can damage and deplete the supply of oocytes stored within the ovary, which predisposes females to infertility and premature menopause later in life. The mechanisms by which radiation induces oocyte damage have not been completely elucidated. The objective of this study was to determine if γ-irradiation changes mitochondrial characteristics in oocytes, possibly contributing to a reduction in oocyte number and quality. Immature oocytes were collected from postnatal day (PN) 9-11 C57Bl6 mice 3, 6 and 24 hours after 0.1 Gy γ-irradiation to monitor acute mitochondrial changes. Oocytes were classified as small (>20 µm) or growing (40-60 µm). Mitochondrial membrane potential was lost in 20% and 44% of small oocytes (~20 µm) at 3 and 6 hours after γ-irradiation, respectively, consistent with the induction of apoptosis. However, mitochondrial mass, distribution and membrane potential in the surviving small oocytes were similar to the non-irradiated controls at both time points. At 24 hours after γ-irradiation, all mitochondrial parameters analysed within immature oocytes were similar to untreated controls. Mitochondrial parameters within growing oocytes were also similar to untreated controls. When mice were superovulated more than 3 weeks after γ-irradiation, there was a significant reduction in the number of mature oocytes harvested compared to controls (Control 18 ± 1 vs 0.1 Gy 4 ± 1, n = 6/16 mice, p < 0.05). There was a slight reduction in mitochondrial mass in mature oocytes after γ-irradiation, though mitochondrial localization, mtDNA copy number and ATP levels were similar between groups. In summary, this study shows that γ-irradiation of pre-pubertal mice is associated with loss of mitochondrial membrane potential in a significant proportion of small immature oocytes and a reduction in the number of mature oocytes harvested from adult mice. Furthermore, these results suggest that immature oocytes that survive γ-irradiation and develop through to ovulation contain mitochondria with normal characteristics. Whether the oocytes that survive radiation and eventually undergo meiosis can support fertility remains to be determined.
Protective roles and mechanisms of polysaccharides from Dendrobium officinal on natural aging-induced premature ovarian failure.
Wu Ya-Yun,Liang Chu-Yan,Liu Ting-Ting,Liang Ying-Min,Li Shi-Jie,Lu Ying-Yu,Liang Jian,Yuan Xin,Li Chu-Jie,Hou Shao-Zhen,Lai Xiao-Ping
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
This study was designed to investigate the pharmacological effects and mechanisms of polysaccharides from Dendrobium officinal (DOP) on premature ovarian failure (POF) in natural aging mice. Fifteen months old female mice (n = 28) and young adult female mice (n = 14, 6 weeks) were used. DOP (70 mg/kg) was administrated to mice by oral gavage for 10 weeks and the protection effects of DOP on ovaries were investigated in vivo. The results showed that DOP reduced body weight, ovary and uterus/body weight parameters to normal level and alleviated ovarian pathological damage. Moreover, DOP could reduce pro-inflammatory cytokines (TNF-α, IL-6) and MDA levels and improve estradiol, SOD, GSH-Px, T-AOC and IL-10 levels in serum. These results suggested that DOP may alleviate the damage caused by aging through the inhibition of the nuclear factor -κB (NF-κB) and p53/Bcl-2-mediate signaling pathways. Moreover, we found that DOP can increase the numbers of mitochondria and endoplasmic reticulum. Moreover, DOP increased the numbers of different stages of follicular cells and improved mitochondrial membrane potential in ovaries. These results indicated that DOP may relieve ovarian damage through the protection of mitochondria in the ovaries. These findings suggest that DOP may be a promising drug for treating POF caused by natural aging in females.
Zuogui Pills inhibit mitochondria-dependent apoptosis of follicles in a rat model of premature ovarian failure.
Peng Huijuan,Zeng Lihua,Zhu Ling,Luo Songping,Xu Limian,Zeng Lei,Li Jing,Liang Qunying,Geng Hongling
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Zuogui Pills (ZGP), which is a classical prescription of Traditional Chinese Medicine (TCM), has been reported to be widely used in the treatment of premature ovarian failure (POF). AIM OF THE STUDY:To investigate the therapeutic effects of ZGP on the treatment of POF induced by chemotherapy, and elucidate the potential molecular mechanism. MATERIALS AND METHODS:Female 8-week-old Sprague-Dawley rats (N = 54) were randomized to six groups, containing the Control group, Model group, three ZGP groups and Triptorelin group which was served as a positive control. The Triptorelin group received triptorelin injection ten days before model establishment by cyclophosphamide. The three ZGP groups (high dose group, medium dose group and low dose group) were given a daily intragastric administration of ZGP at doses of 3.2, 1.6 and 0.8 g/kg for sixty days. We observed the general growth of rats and examed the estrous cycle and the rate of pregnancy, ovarian ultrastructures, follicles and corpora lutea numbers. The serum hormone concentrations were measured by Enzyme-linked immunosorbent assay (ELISA). To explore the molecular mechanism of the effect, gene and protein expression levels of Bax, Bcl-2 and Cyt-c related to apoptosis were determined by quantitative PCR (qPCR), Western Blot and Immunohistochemistry analysis, respectively. RESULTS:After treating with ZGP, though the rate of pregnancy showed no significant difference, the estrous cycle, ovarian ultrastructures, numbers of follicles and corpora lutea were improved significantly. And ZGP led to a significant lower concentration of follicle stimulating hormone (FSH) in the serum, and the concentration of oestradiol (E2) was increased. Furthermore, a significant downregulation of Bax, cytochrome c (Cyt-c), and upregulation of B cell lymphoma/leukemia-2 (Bcl-2) both on gene and protein levels were observed after the administration with ZGP. And effects showed a positive correlation with the dosages. CONCLUSIONS:Our study suggested that ZGP exerted significant effect on POF, which was meditated by inhibiting mitochondria-dependent apoptosis in the follicles.