Mitochondrial Function and Dysfunction in Female Fertility: Biological Mechanisms, Genetic Determinants, and Therapeutic Opportunities - A Review.

Abstract

Female fertility relies on tightly regulated mitochondrial bioenergetics to support oocyte maturation, fertilization, and early embryonic development. Beyond ATP generation, mitochondria orchestrate redox signaling, calcium homeostasis, metabolic-epigenetic coupling, and nuclear-mitochondrial communication, thereby shaping oocyte competence and ovarian longevity. Aging, obesity, metabolic stress, and genetic perturbations disrupt these regulatory networks, leading to redox imbalance, impaired oxidative phosphorylation, altered mitochondrial dynamics, and mitochondrial DNA instability. These changes compromise granulosa cell support, impair meiotic progression, and accelerate ovarian aging, contributing to female infertility disorders such as polycystic ovary syndrome. This review integrates therapeutic strategies that actively reprogram ovarian mitochondrial function rather than merely counteracting damage. Mitochondria-targeted antioxidants-including melatonin, resveratrol, N-acetylcysteine, mitochondria-directed scavengers, and coenzyme Q10 restore redox balance, stabilize mitochondrial dynamics, and enhance oocyte bioenergetics. In parallel, metabolic modulators such as metformin, dapagliflozin, and glucagon-like peptide-1 receptor agonists reprogram ovarian bioenergetics by reshaping substrate utilization, suppressing inflammatory and oxidative signaling, and improving mitochondrial efficiency within the ovary. Collectively, these interventions demonstrate that, positioning mitochondria-centered therapies as promising strategies to preserve fertility and extend the female reproductive health span.