Altered Energy Metabolism, Mitochondrial Dysfunction, and Redox Imbalance Influencing Reproductive Performance in Granulosa Cells and Oocyte During Aging

Abstract

Female fertility decreases during aging. The development of effective therapeutic strategies to address the age-related decline in oocyte quality and quantity and its accurate diagnosis remain major challenges. In this review, we summarize our current understanding of the study of aging and infertility, focusing primarily on the molecular basis of energy metabolism, mitochondrial function, and redox homeostasis in granulosa cells and oocytes, and discuss perspectives on future research directions. Mitochondria serve as a central hub sensing a multitude of physiological processes, including energy production, cellular redox homeostasis, aging, and senescence. Young granulosa cells favor glycolysis and actively produce pyruvate, NADPH, and other metabolites. Oocytes rely on oxidative phosphorylation fueled by nutrients, metabolites, and antioxidants provided by the adjacent granulosa cells. A reduced cellular energy metabolism phenotype, including both aerobic glycolysis and mitochondrial respiration, is characteristic of older female granulosa cells compared with younger female granulosa cells. Aged oocytes become more susceptible to oxidative damage to cells and mitochondria because of further depletion of antioxidant-dependent ROS scavenging systems. Molecular perturbations of gene expression caused by a subtle change in the follicular fluid microenvironment adversely affect energy metabolism and mitochondrial dynamics in granulosa cells and oocytes, further causing redox imbalance and accelerating aging and senescence. Furthermore, recent advances in technology are beginning to identify biofluid molecular markers that may influence follicular development and oocyte quality. Accumulating evidence suggests that redox imbalance caused by abnormal energy metabolism and/or mitochondrial dysfunction is closely linked to the pathophysiology of age-related subfertility.

Keywords: Energy metabolism; Granulosa cells; Mitochondrial function; Oocyte; Redox homeostasis.