Mitochondrial dynamics and miRNA-orchestrated mitophagy in female infertility

Female infertility is gradually being appreciated as a condition driven by mitochondrial dysfunction. Mitochondria play pivotal roles as proximal regulators of oogenesis. This is due to the regulation of ATP production, calcium regulation, redox signaling, and mitochondrial-mediated apoptotic pathways that play a significant part in spindle formation during meiotic segregation of chromosomes. The subsequent disturbances in these pathways bring together elements of damage as well as energy deficiency that influence oocyte development competence. Mitochondrial homeostasis is maintained by highly integrated processes such as fusion, fission, mitophagy, biogenesis, and the mitochondrial unfolded protein response. The key regulatory proteins, such as mitofusin 1, mitofusin 2, optic atrophy protein 1, and DRP1, mediate mitochondrial dynamics under conditions of metabolism and oxidative damage. Dysfunction of these processes gives rise to a fragmented mitochondrial network and overactive PINK1/Parkin-mediated mitophagy pathways that underpin follicle depletion and ovarian aging. MicroRNAs are now recognized to play an essential role in the post-transcriptional regulation of mitochondrial processes and mitophagy in the ovary. Also, abnormal expressions of microRNAs, caused by aging, oxidative stress, and the consequent release of pro-inflammatory cytokines and hormonal dysregulation, act directly on genes involved in the regulation of mitochondrial processes and apoptosis. MicroRNAs including miR-484, miR-30a-5p, miR-146b-5p, and miR-129. This review integrates mechanistic findings from cell, animal, and human studies to explain the regulation of mitochondrial quality control in female infertility by microRNAs, identifying molecular therapeutic targets for development.