Mitochondrial Ca2+ homeostasis in ovarian function and oocyte competence: from molecular transporters to early embryonic development

Mitochondrial Ca 2+ homeostasis is a critical interface connecting ovarian cell signaling, energy metabolism, redox balance, and reproductive competence. Transient Ca 2+ uptake into the mitochondrial matrix activates Ca 2+ -sensitive dehydrogenases, enhances reducing-equivalent generation, and supports oxidative phosphorylation. By contrast, sustained Ca 2+ accumulation promotes reactive oxygen species production, membrane-potential collapse, mitochondrial permeability transition, and cell death. The identification of the mitochondrial calcium uniporter together with its regulators MICU1, MICU2, and EMRE, has established a molecular framework for mitochondrial Ca 2+ influx. NCLX and its interacting protein TMEM65 contribute to Ca 2+ efflux and determine recovery after individual Ca 2+ transients. In ovarian cells and oocytes, endoplasmic reticulum (endoplasmic reticulum)-mitochondria contact sites, including the IP 3 R1-GRP75-VDAC1 axis, couple cytosolic Ca 2+ signals to mitochondrial metabolism. Evidence from mouse, porcine, avian, zebrafish, Xenopus , and sea-urchin models implicates mitochondrial Ca 2+ in follicular-cell survival, oocyte meiotic maturation, fertilization-associated Ca 2+ oscillations, the oocyte-to-embryo transition, and early embryonic development. Obesity, aging, cryopreservation, heavy metals, environmental chemicals, and oxidative stress can disturb this system. However, mitochondrial Ca 2+ dysregulation is not always readily separable from broader mitochondrial or ER dysfunction. Major limitations of the current literature include reliance on non-selective pharmacological agents, incomplete calibration of organelle-targeted indicators, insufficient temporal resolution, interspecies differences, and limited direct evidence from human oocytes. Future studies should integrate cell-type-specific genetic perturbation, quantitative multi-organelle Ca 2+ imaging, mitochondrial bioenergetics, and long-term developmental assessment. Mitochondrial Ca 2+ is a promising mechanistic node and candidate biomarker, but it is not yet a validated clinical target in reproductive medicine.