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

Mitochondrial Ca²⁺ homeostasis is a critical interface connecting ovarian cell signaling, energy metabolism, redox balance, and reproductive competence. Transient Ca²⁺ uptake into the mitochondrial matrix activates Ca²⁺-sensitive dehydrogenases, enhances reducing-equivalent generation, and supports oxidative phosphorylation. By contrast, sustained Ca²⁺ 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 Ca²⁺ influx. NCLX and its interacting protein TMEM65 contribute to Ca²⁺ efflux and determine recovery after individual Ca²⁺ transients. In ovarian cells and oocytes, endoplasmic reticulum (endoplasmic reticulum)-mitochondria contact sites, including the IP₃R1-GRP75-VDAC1 axis, couple cytosolic Ca²⁺ signals to mitochondrial metabolism. Evidence from mouse, porcine, avian, zebrafish, Xenopus, and sea-urchin models implicates mitochondrial Ca²⁺ in follicular-cell survival, oocyte meiotic maturation, fertilization-associated Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ imaging, mitochondrial bioenergetics, and long-term developmental assessment. Mitochondrial Ca²⁺ is a promising mechanistic node and candidate biomarker, but it is not yet a validated clinical target in reproductive medicine.