FIGURE 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Source publication
Mitochondrial dynamics (fission and fusion) are essential physiological processes for mitochondrial metabolic function, mitochondrial redistribution, and mitochondrial quality control. Various proteins are involved in regulating mitochondrial dynamics. Aberrant expression of these proteins interferes with mitochondrial dynamics and induces a range...
Contexts in source publication
Context 1
... in MFN2 affects this interaction, leading to impairment in axonal mitochondrial transport ( Adebayo et al., 2021). Early onset is often associated with more severe cases, resembling dominant optic atrophy caused by OPA1 mutations (Hamedani et al., 2021). Besides, deletion of MFN2 is perinatally lethal to the embryo in both murine and canine models, likely due to lack of protein stability. ...
Context 2
... summary, the homeostasis of mitochondrial dynamics is a multiprotein regulation physiological process (Figure 1). Therefore, abnormalities of relevant genes or proteins in somatic cells or germ cells will lead to disorders of the mitochondrial dynamic balance due to impaired mitochondrial morphology and function, leading to organ dysfunction and diseases. ...
Citations
... First of all, the function of mitochondria in porcine oocytes was studied. Mitochondrial dysfunction can destroy the female reproductive function of oocyte maturation, fertilization and embryonic development [45]. Strong evidence indicated that ZEA damaged Sertoli cells through reducing mitochondrial membrane potential and altering mitochondrial structure [46]. ...
Background:
Zearalenone (ZEA) widely exists in moldy grains, which seriously destroys the fertility of females. Isorhamnetin, a natural flavonoid, has extensive of pharmacological activities. However, the beneficial effect and the underlying molecular mechanism of isorhamnetin involvement in ZEA-induced porcine oocyte damage have not been investigated.
Methods:
Oocytes were treated with different concentrations of ZEA (3, 5, 8 and 10 μmol/L) and isorhamnetin (5, 10, 20 and 30 μmol/L) for 44 h at 39 ℃. ZEA (5 μmol/L) and isorhamnetin (10 μmol/L) were selected for subsequent studies. Polar body exclusion rate, apoptosis rate and apoptosis related proteins, ROS levels and SOD2 protein, mitochondrial membrane potential and distribution, endoplasmic reticulum distribution and proteins expression, and PI3K, Akt and p-Akt proteins expression of oocytes were detected. In addition, the effect of PI3K antagonist (LY294002) on oocyte nuclear maturation and apoptosis were used to determine the involvement of PI3K/Akt signaling pathway.
Results:
Our findings showed that ZEA exposure damaged oocytes and isorhamnetin therapy restored the developmental capability of porcine oocytes. Isorhamnetin promoted polar body extrusion rate to rescue ZEA-induced meiotic arrest in porcine oocytes. Isorhamnetin alleviated ZEA-induced oxidative stress by stimulating SOD2 protein expression and inhibiting ROS production. Moreover, isorhamnetin enhanced normal mitochondrial distribution and mitochondrial membrane potential to prevent mitochondrial dysfunction induced by ZEA. Changing the expression of endoplasmic reticulum stress-related marker proteins (CHOP, GRP78) and the distribution rate of normal endoplasmic reticulum showed that isorhamnetin relieved ZEA-caused endoplasmic reticulum stress. Mechanistically, isorhamnetin decreased Bax/Bcl-2 protein expression and inhibited ZEA-induced apoptosis through PI3K/Akt signaling pathway.
Conclusions:
Collectively, these results suggest that isorhamnetin protects oocytes from ZEA-caused damage through PI3K/Akt signaling pathway, which enhances meiotic maturation and mitochondrial function, and inhibits early apoptosis, oxidative stress and endoplasmic reticulum stress in porcine oocytes. Our study provides a new strategy for solving the reproductive toxicity induced by ZEA and treating woman infertility. A possible mechanism by which isorhamnetin protected porcine oocytes from ZEA-induced damage. Isorhamnetin inhibited meiosis arrest and apoptosis of porcine oocytes induced by ZEA through the PI3K/Akt signaling pathway. Moreover, isorhamnetin repaired ZEA-induced oocyte damage by alleviating oxidative stress, mitochondrial dysfunction and ER stress.
... This is driven by a variety of nuclear genes, which encode mitochondrial proteins that are responsible for the replication and transcription of the mitochondrial genome (Hock and Kralli, 2009;Popov, 2020). Mitochondria and their roles in oocytes are rather well studied (Udagawa and Ishihara, 2020;Zou et al., 2021). In contrast, mitochondria in follicular GCs and luteal cells, and their structure, dynamics and roles are only rudimentarily known, especially in human cells. ...
In the ovary, proliferation and differentiation of granulosa cells (GCs) drive follicular growth. Our immunohistochemical study in a non-human primate, the Rhesus monkey, showed that the mitochondrial activity marker protein cytochrome c oxidase subunit 4 (COX4) increases in GCs in parallel to follicle size, and furthermore, its intracellular localization changes. This suggested that there is mitochondrial biogenesis and trafficking, and implicates the actions of gonadotropins, which regulate follicular growth and ovulation. Human KGN cells, i.e. granulosa tumour cells, were therefore used to study these possibilities. To robustly elevate cAMP, and thereby mimic the actions of gonadotropin, we used forskolin (FSK). FSK increased the cell size and the amount of mitochondrial DNA of KGN cells within 24 h. As revealed by MitoTrackerTM experiments and ultrastructural 3D reconstruction, FSK treatment induced the formation of elaborate mitochondrial networks. H89, a protein kinase A (PKA) inhibitor, reduced the network formation. A proteomic analysis indicated that FSK elevated thelevels of regulators of the cytoskeleton, among others (data available via ProteomeXchange with identifier PXD032160). The steroidogenic enzyme CYP11A1 (Cytochrome P450 Family 11 Subfamily A Member 1), located in mitochondria, was more than three-fold increased by FSK, implying that the cAMP/PKA-associated structural changes occur in parallel with the acquisition of steroidogenic competence of mitochondria in KGN cells. In summary, the observations show increases in mitochondria and intracellular trafficking of mitochondria in GCs during follicular growth and indicate that they may partially be under the control of gonadotropins and cAMP. In line with this, increased cAMP in KGN cells profoundly affected mitochondrial dynamics in a PKA-dependent manner and implicated cytoskeletal changes.
... Within these networks, hundreds, thousands, or even up to ten thousand individual organelles are fused. Surprisingly, in model organisms as D. melanogaster, mouse, and C. elegans, although the changes in mitochondrial morphology during oogenesis were described many times, and the mechanisms of fusion and fission events were examined, there is no mention of similar extensive networks [84][85][86][87][88]. In D. melanogaster, for example, during germ-line cyst formation and cystocyte divisions, the number of mitochondria increases about eightfold and mitochondrial volume rises from 14-to 20-fold increase [89]. ...
The syncytial groups of germ cells (germ-line cysts) forming in ovaries of clitellate annelids are an attractive model to study mitochondrial stage-specific changes. Using transmission electron microscopy, serial block-face scanning electron microscopy, and fluorescent microscopy, we analyzed the mitochondria distribution and morphology and the state of membrane potential in female cysts in Enchytraeus albidus. We visualized in 3D at the ultrastructural level mitochondria in cysts at successive stages: 2-celled, 4-celled, 16-celled cysts, and cyst in advanced oogenesis. We found that mitochondria form extensive aggregates – they are fused and connected into large and branched mitochondrial networks. The most extensive networks are formed with up to 10,000 fused mitochondria, whereas individual organelles represent up to 2% of the total mitochondrial volume. We classify such morphology of mitochondria as a dynamic hyperfusion state, and suggest that it can maintain their high activity and intensifies the process of cellular respiration within the syncytial cysts. We found some individual mitochondria undergoing degradation, which implies that damaged mitochondria are removed from networks for their final elimination. As it was shown that growing oocytes possess less active mitochondria than the nurse cells, it suggests that the high activity of mitochondria in the nurse cells and their dynamic hyperfusion state serve the needs of the growing oocyte. Additionally, we measured by calorimetry the total antioxidant capacity of germ-line cysts in comparison to somatic tissue, and it suggests that antioxidative defense systems, together with mitochondrial networks, can effectively protect germ-line mitochondria from damage.
Irreversible cryogenic damage caused by oocyte vitrification limits its widespread use in female fertility preservation. In recent years, nanoparticles (NPs) have gained great attention as potential alternatives in protecting oocytes against cryoinjuries. In this paper, a novel composite nanoparticle, poly (lactic-co-glycolic acid)-resveratrol (PLGA-RES) was designed to improve the biocompatibility and sustained release properties by encapsulating natural antioxidant RES into PLGA NPs. Firstly, biotoxicity and oxidation resistance of PLGA-RES were determined, and the results showed that PLGA-RES had nontoxic effect on oocyte survival during in vitro maturation (IVM) (97.08% ± 0.24% vs. 98.89% ± 1.11%, p > 0.05). Notably, PLGA-RES even increased maturation (65.10% ± 4.11% vs. 52.85% ± 2.87%, p < 0.05) and blastocyst rate (56.13% ± 1.36% vs. 40.91% ± 5.85%, p < 0.05). Moreover, the reduced reactive oxygen species (ROS) level (13.49 ± 2.30 vs. 34.07 ± 3.30, p < 0.01), increased glutathione (GSH) (44.13 ± 1.57 vs. 37.62 ± 1.79, p < 0.01) and elevated mitochondrial membrane potential (MMP) levels (43.10 ± 1.81 vs. 28.52 ± 1.25, p < 0.01) were observed in oocytes treated with PLGA-RES when compared with that of the control group. Subsequently, the role of PLGA-RES played in oocytes during vitrification was systematically evaluated. The results showed that the addition of PLGA-RES during vitrification and thawing significantly improved the survival rate (80.42% ± 1.97% vs. 75.37% ± 1.3%, p < 0.05). Meanwhile, increased GSH (15.09 ± 0.86 vs. 14.51 ± 0.78, p < 0.01) and mitochondrial membrane potential (22.56 ± 3.15 vs. 6.79 ± 0.60, p < 0.01), decreased reactive oxygen species levels (52.11 ± 2.95 vs. 75.41 ± 7.23, p < 0.05) and reduced mitochondrial abnormality distribution rate (25.00% ± 0.29% vs. 33.33% ± 1.15%, p < 0.01) were assessed in vitrified MII oocytes treated with PLGA-RES. Furthermore, transcriptomic analyses demonstrated that PLGA-RES participated in endocytosis and PI3K/AKT/mTOR pathway regulation, which was verified by the rescued expression of ARRB2 and ULK3 protein after PLGA-RES treatment. In conclusion, PLGA-RES exhibited potent antioxidant activity, and could be used as an efficacious strategy to improve the quality of vitrified oocytes.
Mitochondrial diseases (MDs) are genetic and clinical heterogeneous diseases caused by mitochondrial oxidative phosphorylation defects. It is not only one of the most common genetic diseases, but also the only genetic disease involving two different genomes in humans. As a result of the complicated genetic condition, the pathogenesis of MDs is not entirely elucidated at present, and there is a lack of effective treatment in the clinic. Establishing the ideal animal models is the critical preclinical platform to explore the pathogenesis of MDs and to verify new therapeutic strategies. However, the development of animal modeling of mitochondrial DNA (mtDNA)-related MDs is time-consuming due to the limitations of physiological structure and technology. A small number of animal models of mtDNA mutations have been constructed using cell hybridization and other methods. However, the diversity of mtDNA mutation sites and clinical phenotypes make establishing relevant animal models tricky. The development of gene editing technology has become a new hope for establishing animal models of mtDNA-related mitochondrial diseases.
BACKGROUND: It was demonstrated that external stress, such as in vitro maturation (IVM) and vitrification process can induce significantly reduced development capacity in oocytes. Previous studies indicated that antioxidants play a pivotal part in the acquisition of adaptation in changed conditions. At present, the role of the natural potent antioxidant PCB2 in response to IVM and vitrification during ovine oocyte manipulation has not been explored. OBJECTIVE: To investigate whether PCB2 treatment could improve the developmental potential of ovine oocytes under IVM and vitrification stimuli. MATERIALS AND METHODS: The experiment was divided into two parts. Firstly, the effect of PCB2 on the development of oocytes during IVM was evaluated. Unsupplem ented and 5 μg/mL PCB2 -supplemented in the IVM solution were considered as control and experimental groups (C + 5 μg/mL PCB2). The polar body extrusion (PBE) rate, mitochondrial membrane potential (MMP), ATP, reactive oxygen species (ROS) levels and early apoptosis of oocytes were measured after IVM. Secondly, we further determine whether PCB2 could improve oocyte quality under vitrification stress. The survival rate, PBE rate and early apoptosis of oocytes were compared between fresh group, vitrified group and 5 μg/mL PCB2 -supplemented in the IVM solution after vitrification (V + 5μg/mL PCB2). RESULTS: Compared to the control group, adding PCB2 significantly increased PBE rate (79.4% vs. 62.8%, P < 0.01) and MMP level (1.9 ± 0.08 vs. 1.3 ± 0.04, P < 0.01), and decreased ROS level (47.1 ± 6.3 vs. 145.3 ± 8.9, P < 0.01). However, there was no significant difference in ATP content and early apoptosis. Compared to the fresh group, vitrification significantly reduced oocytes viability (43.0% vs. 90.8%, P < 0.01) as well as PBE rate (24.2% vs. 60.6%, P < 0.05). However, 5 μg/mL PCB2-supplemention during maturation had no effect on survival, PBE or early apoptosis in vitrified oocytes. CONCLUSION: PCB2 could effectively antagonise the oxidative stress during IVM and promote oocyte development.
Accumulating evidences revealed the connections between arsenic exposure and mitochondrial dysfunctions induced reproductive toxicology. Meanwhile, production declines were found in livestock suffering from arsenic exposure. However, the connections between arsenic exposure and livestock meiotic defects remain unclear. In this study, the effects of sodium arsenite (NaAsO2) exposure during the in vitro maturation (IVM) on the meiotic potentials of ovine oocytes were analyzed. Furthermore, the effects of glutathione (GSH) supplementation on the meiotic defects of NaAsO2 exposed ovine oocytes were investigated by the assay of nuclear maturation, spindle organization, chromosome alignment, cytoskeleton assembly, cortical granule (CGs) dynamics, mitochondrial dysfunctions, reactive oxygen species (ROS) accumulation, oxidative DNA damages, cellular apoptosis, epigenetic modifications and fertilization capacities. The results showed that the meiotic defects of NaAsO2 exposed ovine oocytes were effectively ameliorated by the GSH supplementation via the inhibition of mitochondrial dysfunctions, which not only promoted the nuclear maturation, spindle organization, chromosome alignment, cytoskeleton assembly, CGs dynamic and fertilization capacities, but also inhibited the ROS accumulation, oxidative DNA damages and apoptosis of ovine MII oocytes. The abnormal expressions of 5mC, H3K4me3 and H3K9me3 in NaAsO2 exposed ovine oocytes, indicating the abnormal epimutations of DNA methylation and histone methylation, were also effectively ameliorated by the GSH supplementation. Taken together, this study confirmed the connections between arsenic exposure and meiotic defects of ovine oocytes. Meanwhile, the effects of GSH supplementation on the developmental competence of livestock oocytes, especially for these suffering from arsenic exposure were also founded, benefiting the extended researches for the GSH applications.
