Research Progress on the Impact of Mitophagy on Oocyte
LI Na1, GAO Qian2, CUI Zhao-Kang3, HUANG Guang-Jun1, AN Zhen-Jiang1, MIAO Yi-Long1,*
1 College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; 2 College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; 3 Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
Abstract：Mitochondrial autophagy plays a crucial role in cellular health and development. As a cellular autophagy mechanism, mitochondrial autophagy is responsible for the removal of damaged or dysfunctional mitochondria, ensuring cellular energy supply and metabolic balance. This article reviewed the latest research advancements in mitochondrial autophagy, focusing on the interplay between the PINK1/Parkin-dependent ubiquitin pathway and the ubiquitin-independent receptor-mediated autophagy mechanism. It also discussed the significance of mitochondrial autophagy in maintaining normal functions at the metabolic level in oocytes and in preserving mitochondrial quality in aging oocytes. Research indicated that mitochondrial autophagy not only effectively clears mutated mitochondrial DNA but also reduced oxidative stress, thereby enhancing the developmental potential of oocytes. By systematically summarizing the critical role of mitochondrial autophagy in oocyte development, this article provides new perspectives and strategies for optimizing reproductive technologies in both humans and animals, advancing further research and applications in the field.
李娜, 高倩, 崔兆康, 黄广军, 安振江, 苗义龙. 线粒体自噬对卵母细胞影响的研究进展[J]. 农业生物技术学报, 2025, 33(8): 1852-1862.
LI Na, GAO Qian, CUI Zhao-Kang, HUANG Guang-Jun, AN Zhen-Jiang, MIAO Yi-Long. Research Progress on the Impact of Mitophagy on Oocyte. 农业生物技术学报, 2025, 33(8): 1852-1862.
[1] Agarwal A, Aponte-Mellado A, Premkumar B J, et al.2012. The effects of oxidative stress on female reproduction: A review[J]. Reproductive Biology and Endocrinology, 10: 49. [2] Allen G F, Toth R, James J, et al.2013. Loss of iron triggers PINK1/Parkin-independent mitophagy[J]. EMBO Reports, 14(12): 1127-1135. [3] Anderson S, Bankier A T, Barrell B G, et al.1981. Sequence and organization of the human mitochondrial genome[J]. Nature, 290(5806): 457-465. [4] Arbeithuber B, Cremona M A, Hester J, et al.2022. Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues[J]. Proceedings of the National Academy of Sciences of the USA, 119: e2118740119. [5] Bentov Y, Casper R F2013. The aging oocyte-can mitochondrial function be improved?[J]. Fertility and Sterility, 99(1): 18-22. [6] Bertolin G, Ferrando-Miguel R, Jacoupy M, et al.2013. The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance[J]. Autophagy, 9(11): 1801-1817. [7] Bootman M D, Chehab T, Bultynck G, et al.2018. The regulation of autophagy by calcium signals: Do we have a consensus?[J]. Cell Calcium, 70: 32-46. [8] Caballero B, Vega-Naredo I, Sierra V, et al.2008. Favorable effects of a prolonged treatment with melatonin on the level of oxidative damage and neurodegeneration in senescence-accelerated mice[J]. Journal of Pineal Research, 45(3): 302-311. [9] Caballero B, Vega-Naredo I, Sierra V, et al.2009. Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice[J]. Journal of Pineal Research, 46(1): 106-114. [10] Calabrese G, Morgan B, Riemer J2017. Mitochondrial glutathione: Regulation and functions[J]. Antioxid Redox Signal, 27(15): 1162-1177. [11] Cárdenas C, Miller R A, Smith I, et al.2010. Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria[J]. Cell, 142(2): 270-283. [12] Cen X, Chen Y, Xu X, et al.2020. Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer's disease mouse model[J]. Nature Communication, 11(1): 5731. [13] Chandel N S2014. Mitochondria as signaling organelles[J]. BMC Biology, 12: 34. [14] Chatel-Chaix L, Cortese M, Romero-Brey I, et al.2016. Dengue virus perturbs mitochondrial morphodynamics to dampen innate immune responses[J]. Cell Host & Microbe, 20(3): 342-356. [15] Chen M, Chen Z, Wang Y, et al.2016. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy[J]. Autophagy, 12(4): 689-702. [16] Chen Y, Dorn G W 2nd.2013. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria[J]. Science, 340(6131): 471-475. [17] Choksi K B, Nuss J E, Boylston W H, et al.2007. Age-related increases in oxidatively damaged proteins of mouse kidney mitochondrial electron transport chain complexes[J]. Free Radical Biology and Medicine, 43(10): 1423-1438. [18] Cota V, Sohrabi S, Kaletsky R, et al.2022. Oocyte mitophagy is critical for extended reproductive longevity[J]. PLOS Genetics, 18(9): e1010400. [19] Cummins J M.2004. The role of mitochondria in the establishment of oocyte functional competence[J]. European Journal of Obstetrics, Gynecology, and Reproductive Biology, (115 Suppl): S23-S29. [20] Deneubourg C, Ramm M, Smith L J, et al.2022. The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy[J]. Autophagy, 18(3): 496-517. [21] Deter R L, De Duve C.1967. Influence of glucagon, an inducer of cellular autophagy, on some physical properties of rat liver lysosomes[J]. Journal of Cell Biology, 33(2): 437-449. [22] Di Rienzo M, Romagnoli A, Ciccosanti F, et al.2022. AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability[J]. Autophagy, 18(8): 1752-1762. [23] Egan D F, Shackelford D B, Mihaylova M M, et al.2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy[J]. Science, 331(6016): 456-461. [24] Eisenberg T, Abdellatif M, Schroeder S, et al.2016. Cardioprotection and lifespan extension by the natural polyamine spermidine[J]. Nature Medicine, 22(12): 1428-1438. [25] Giorgi C, Marchi S, Pinton P2018. The machineries, regulation and cellular functions of mitochondrial calcium[J]. Nature Reviews: Molecular Cell Biology, 19(11): 713-730. [26] Halliwell B, Cross C E1994. Oxygen-derived species: their relation to human disease and environmental stress[J]. Environmental Health Perspectives,(102 Suppl) 10: 5-12. [27] Han J Y, Kang M J, Kim K H, et al.2015. Nitric oxide induction of Parkin translocation in PTEN-induced putative kinase 1 (PINK1) deficiency: Functional role of neuronal nitric oxide synthase during mitophagy[J]. Journal of Biological Chemistry, 290(16): 10325-10335. [28] Harnett M M, Pineda M A, Latré De Laté P, et al.2017. From Christian de Duve to Yoshinori Ohsumi: More to autophagy than just dining at home[J]. Biomedical Journal, 40(1): 9-22. [29] Hauswirth W W, Laipis P J1982. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows[J]. Proceedings of the National Academy of Sciences of the USA, 79(15): 4686-4690. [30] He A, Chen X, Tan M, et al.2020. Acetyl-CoA derived from hepatic peroxisomal β-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation[J]. Molecular Cell, 79(1): 30-42. [31] He H, Huang W, Xiong L, et al.2024. FUNDC1-mediated mitophagy regulates photodamage independently of the PINK1/Parkin-dependent pathway[J]. Free Radical Biology and Medicine, 225: 630-640. [32] Head E, Liu J, Hagen T M, et al.2002. Oxidative damage increases with age in a canine model of human brain aging[J]. Journal of Neurochemistry, 82(2): 375-381. [33] Herzig S, Shaw R J.2018. AMPK: Guardian of metabolism and mitochondrial homeostasis[J]. Nature Reviews: Molecular Cell Biology, 19(2): 121-135. [34] Hoshino A, Wang W J, Wada S, et al.2019. The ADP/ATP translocase drives mitophagy independent of nucleotide exchange[J]. Nature, 575(7782): 375-379. [35] Ito J, Shirasuna K, Kuwayama T, et al.2020. Resveratrol treatment increases mitochondrial biogenesis and improves viability of porcine germinal-vesicle stage vitrified-warmed oocytes[J]. Cryobiology, 93: 37-43. [36] Jain A, Lamark T, Sjøttem E, et al.2010. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription[J]. Journal of Biological Chemistry, 285(29): 22576-22591. [37] Jewell J L, Russell R C, Guan K L2013. Amino acid signalling upstream of mTOR[J]. Nature Reviews: Molecular Cell Biology, 14(3): 133-139. [38] Jin S M, Youle R J.2012. PINK1- and Parkin-mediated mitophagy at a glance[J]. Journal of Cell Science, 125(Pt4): 795-799. [39] Jin X, Wang K, Wang L, et al.2022. RAB7 activity is required for the regulation of mitophagy in oocyte meiosis and oocyte quality control during ovarian aging[J]. Autophagy, 18(3): 643-660. [40] Jones D P.2008. Radical-free biology of oxidative stress[J]. American Journal of Physiology: Cell Physiology, 295(4): C849-868. [41] Kim J Y, Lee S H, Bae I H, et al.2018. Pyruvate protects against cellular senescence through the control of mitochondrial and lysosomal function in dermal fibroblasts[J]. Journal of Investigative Dermatology, 138(12): 2522-2530. [42] Kim K H, Kim E Y, Ko J J, et al.2019. Gas6 is a reciprocal regulator of mitophagy during mammalian oocyte maturation[J]. Scientific Reports, 9(1): 10343. [43] Kirillova A, Smitz J E J, Sukhikh G T, et al.2021. The role of mitochondria in oocyte maturation[J]. Cells, 10(9): 2484. [44] Koentjoro B, Park J S, Sue C M.2017. Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson's disease[J]. Scientific Reports, 7: 44373. [45] Koh E, Kim Y K, Shin D, et al.2018. MPC1 is essential for PGC-1α-induced mitochondrial respiration and biogenesis[J]. Biochemical Journal, 475(10): 1687-1699. [46] Kregel K C, Zhang H J2007. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations[J]. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 292(1): R18-36. [47] Landes T, Emorine L J, Courilleau D, et al.2010. The BH3-only Bnip3 binds to the dynamin Opa1 to promote mitochondrial fragmentation and apoptosis by distinct mechanisms[J]. EMBO Report, 11(6): 459-465. [48] Lazarou M, Jin S M, Kane L A, et al.2012. Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin[J]. Developmental Cell, 22(2): 320-333. [49] Li Y, Chen Y.2019. AMPK and autophagy[J]. Advances in Experimental Medicine and Biology, 1206: 85-108. [50] Liu P, Demple B.2010. DNA repair in mammalian mitochondria: Much more than we thought?[J]. Environmental and Molecular Mutagenesis, 51(5): 417-426. [51] Liu S, Lu B.2010. Reduction of protein translation and activation of autophagy protect against PINK1 pathogenesis in Drosophila melanogaster[J]. PLOS Genetics, 6(12): e1001237. [52] Lord T, Aitken R J.2013. Oxidative stress and ageing of the post-ovulatory oocyte[J]. Reproduction, 146(6): R217-227. [53] Lv M, Wang C, Li F, et al.2017. Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy[J]. Protein Cell, 8(1): 25-38. [54] Maddison D C, Alfonso-Núñez M, Swaih A M, et al.2020. A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics[J]. PLOS Genetics, 16(11): e1009129. [55] Madeo F, Eisenberg T, Pietrocola F, et al.2018. Spermidine in health and disease[J]. Science, 359(6374): eaan2788. [56] Maeda A, Inoue N, Matsuda-Minehata F, et al.2007. The role of interleukin-6 in the regulation of granulosa cell apoptosis during follicular atresia in pig ovaries[J]. Journal of Reproduction and Development, 53(3): 481-490. [57] Malaviya R, Laskin J D, Laskin D L2014. Oxidative stress-induced autophagy: Role in pulmonary toxicity[J]. Toxicology and Applied Pharmacology, 275(2): 145-151. [58] May-Panloup P, Boucret L, Chao De La Barca J M, et al.2016. Ovarian ageing: the role of mitochondria in oocytes and follicles[J]. Human Reproduction Update, 22(6): 725-743. [59] Meng Y, Qiu L, Zeng X, et al.2022. Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy[J]. Signal Transduct Target Ther, 7(1): 388. [60] Miao Y L, Kikuchi K, Sun Q Y, et al.2009. Oocyte aging: Cellular and molecular changes, developmental potential and reversal possibility[J]. Human Reproduction Update, 15(5): 573-585. [61] Mizushima N, Komatsu M.2011. Autophagy: Renovation of cells and tissues[J]. Cell, 147(4): 728-741. [62] Moore M N.2008. Autophagy as a second level protective process in conferring resistance to environmentally-induced oxidative stress[J]. Autophagy, 4(2): 254-256. [63] Moyzis A G, Lally N S, Liang W, et al.2022. Mcl-1 Differentially regulates autophagy in response to changes in energy status and mitochondrial damage[J]. Cells, 11(9):1469. [64] Nagi M, Tanabe K, Nakayama H, et al.2016. Iron-depletion promotes mitophagy to maintain mitochondrial integrity in pathogenic yeast Candida glabrata[J]. Autophagy, 12(8): 1259-1271. [65] Ohsumi Y.2014. Historical landmarks of autophagy research[J]. Cell Research, 24(1): 9-23. [66] Okatsu K, Kimura M, Oka T, et al.2015. Unconventional PINK1 localization to the outer membrane of depolarized mitochondria drives Parkin recruitment[J]. Journal of Cell Science, 128(5): 964-978. [67] Pasquariello R, Ermisch A F, Silva E, et al.2019. Alterations in oocyte mitochondrial number and function are related to spindle defects and occur with maternal aging in mice and humans[J]. Biology of Reproduction, 100(4): 971-981. [68] Peng W, Wong Y C, Krainc D2020. Mitochondria-lysosome contacts regulate mitochondrial Ca(2+) dynamics via lysosomal TRPML1[J]. Proceedings of the National Academy of Sciences of the USA, 117(32): 19266-19275. [69] Perciavalle R M, Stewart D P, Koss B, et al.2012. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration[J]. Nature Cell Biology, 14(6): 575-583. [70] Pierce S B, Chisholm K M, Lynch E D, et al.2011. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome[J]. Proceedings of the National Academy of Sciences of the USA, 108(16): 6543-6548. [71] Pietrocola F, Galluzzi L, Bravo-San Pedro J M, et al.2015. Acetyl coenzyme A: A central metabolite and second messenger[J]. Cell Metabolism, 21(6): 805-821. [72] Pikó L, Taylor K D.1987. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos[J]. Developmental Biology, 123(2): 364-374. [73] Polyakov V Y, Soukhomlinova M Y, Fais D.2003. Fusion, fragmentation, and fission of mitochondria[J]. Biochemistry (Mosc.), 68(8): 838-849. [74] Qi Y, Qiu Q, Gu X, et al.2016. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts[J]. Scientific Reports, 6: 24700. [75] Richardson D R, Lane D J, Becker E M, et al.2010. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol[J]. Proceedings of the National Academy of Sciences of the USA, 107(24): 10775-10782. [76] Rodríguez-Vargas J M, Ruiz-Magaña M J, Ruiz-Ruiz C, et al.2012. ROS-induced DNA damage and PARP-1 are required for optimal induction of starvation-induced autophagy[J]. Cell Research, 22(7): 1181-1198. [77] Safiulina D, Kuum M, Choubey V, et al.2019. Miro proteins prime mitochondria for Parkin translocation and mitophagy[J]. EMBO Journal, 38(2): e99384. [78] Salazar C, Ruiz-Hincapie P, Ruiz L M2018. The interplay among PINK1/PARKIN/Dj-1 network during mitochondrial quality control in cancer biology: Protein interaction analysis[J]. Cells, 7(10): 154. [79] Santos T A, El Shourbagy S, St John J C.2006. Mitochondrial content reflects oocyte variability and fertilization outcome[J]. Fertility and Sterility, 85(3): 584-591. [80] Scheper G C, Van Der Klok T, Van Andel R J, et al.2007. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation[J]. Nature Genetics, 39(4): 534-539. [81] Schiavi A, Maglioni S, Palikaras K, et al.2015. Iron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C. elegans[J]. Current Biology, 25(14): 1810-1822. [82] Schieber M, Chandel N S.2014. ROS function in redox signaling and oxidative stress[J]. Current Biology, 24(10): R453-462. [83] Schofield J H, Schafer Z T.2021. Mitochondrial reactive oxygen species and mitophagy: A complex and nuanced relationship[J]. Antioxid Redox Signal, 34(7): 517-530. [84] Sharpe A J, Mckenzie M.2018. Mitochondrial fatty acid oxidation disorders associated with short-chain enoyl-CoA hydratase (ECHS1) deficiency[J]. Cells, 7(6): 46. [85] Shen Q, Liu Y, Li H, et al.2021. Effect of mitophagy in oocytes and granulosa cells on oocyte quality[J]. Biology of Reproduction, 104(2): 294-304. [86] Sies H.1997. Oxidative stress: Oxidants and antioxidants[J]. Experimental Physiology, 82: 291-295. [87] Stolz A, Ernst A, Dikic I.2014. Cargo recognition and trafficking in selective autophagy[J]. Nature Cell Biology, 16(6): 495-501. [88] Strappazzon F, Nazio F, Corrado M, et al.2015. AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1[J]. Cell Death and Differentiation, 22(3): 419-432. [89] Su L, Zhang J, Gomez H, et al.2023. Mitochondria ROS and mitophagy in acute kidney injury[J]. Autophagy, 19(2): 401-414. [90] Tan J X, Finkel T.2020. Mitochondria as intracellular signaling platforms in health and disease[J]. Journal of Cell Biology, 219(5): e202002179. [91] Van Blerkom J.2011. Mitochondrial function in the human oocyte and embryo and their role in developmental competence[J]. Mitochondrion, 11(5): 797-813. [92] Van Goethem G, Dermaut B, Löfgren A, et al.2001. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions[J]. Nature Genetics, 28(3): 211-212. [93] Wang L, Cho Y L, Tang Y, et al.2018. PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-Parkin-mediated mitophagy[J]. Cell Research, 28(8): 787-802. [94] Wang R.2012. Physiological implications of hydrogen sulfide: A whiff exploration that blossomed[J]. Physiological Reviews, 92(2): 791-896. [95] Wang S, Long H, Hou L, et al.2023. The mitophagy pathway and its implications in human diseases[J]. Signal Transduct Target Ther, 8(1): 304. [96] Wang X, Schwarz T L.2009. The mechanism of Ca2+ -dependent regulation of kinesin-mediated mitochondrial motility[J]. Cell, 136(1): 163-174. [97] Ward D M, Cloonan S M.2019. Mitochondrial iron in human health and disease[J]. Annual Review of Physiology, 81: 453-482. [98] Wu W, Tian W, Hu Z, et al.2014. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy[J]. EMBO Report, 15(5): 566-575. [99] Xia H G, Zhang L, Chen G, et al.2010. Control of basal autophagy by calpain1 mediated cleavage of ATG5[J]. Autophagy, 6(1): 61-66. [100] Yao Z, Delorme-Axford E, Backues S K, et al.2015. Atg41/Icy2 regulates autophagosome formation[J]. Autophagy, 11(12): 2288-2299. [101] Zhang J.2013. Autophagy and mitophagy in cellular damage control[J]. Redox Biology, 1(1): 19-23. [102] Zhang M, Liang C, Chen X, et al.2024. Interplay between microglia and environmental risk factors in Alzheimer's disease[J]. Neural Regeneration Research, 19(8): 1718-1727. [103] Zhang T, Liu Q, Gao W, et al.2022. The multifaceted regulation of mitophagy by endogenous metabolites[J]. Autophagy, 18(6): 1216-1239. [104] Zhang W2021. The mitophagy receptor FUN14 domain-containing 1 (FUNDC1): A promising biomarker and potential therapeutic target of human diseases[J]. Genes & Diseases, 8(5): 640-654. [105] Zhang Y, Bai J, Cui Z, et al.2023. Polyamine metabolite spermidine rejuvenates oocyte quality by enhancing mitophagy during female reproductive aging[J]. Nature Aging, 3(11): 1372-1386. [106] Zhong D, Wang R, Zhang H, et al.2023. Induction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity[J]. Nature Communication, 14(1): 3997. [107] Zhou H, Li D, Zhu P, et al.2017. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARγ/FUNDC1/mitophagy pathways[J]. Journal of Pineal Research, 63: 142-356. [108] Zhu H L, Shi X T, Xu X F, et al.2021. Melatonin protects against environmental stress-induced fetal growth restriction via suppressing ROS-mediated GCN2/ATF4/BNIP3-dependent mitophagy in placental trophoblasts[J]. Redox Biology, 40: 101854. [109] Zhu Y, Han X Q, Sun X J, et al.2020. Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy[J]. Apoptosis, 25(5-6): 321-340. [110] Zhu Y, Ji J J, Yang R, et al.2019. Lactate accelerates calcification in VSMCs through suppression of BNIP3-mediated mitophagy[J]. Cellular Signalling, 58: 53-64. [111] Zorov D B, Juhaszova M, Sollott S J.2014. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release[J]. Physiological Reviews, 94(3): 909-950
