Crosstalk collapse: mitochondria-centric organelle network disruption in ovarian aging.

Abstract

Ovarian aging defines the reproductive lifespan of females and exerts profound systemic effects on metabolism and overall health. However, its molecular basis remains incompletely understood. Traditional research has focused primarily on mitochondrial dysfunction, whereas emerging evidence indicates that ovarian aging involves a progressive collapse of a mitochondria-centered organelle interaction network. Mitochondria dynamically communicate with the endoplasmic reticulum, lysosomes, peroxisomes, lipid droplets, and the nucleus through membrane contact sites, coordinating energy metabolism, lipid trafficking, calcium signaling, redox balance, and epigenetic regulation. The disruption of these interactions results in excessive reactive oxygen species generation, defective steroidogenesis, impaired quality control, and transcriptional dysregulation, ultimately driving oocyte deterioration and follicular failure. Here, we propose the "Organelle Interaction Network Disruption Model" of ovarian aging, which integrates recent mechanistic insights into a unifying conceptual framework. This model elucidates the dynamic breakdown of inter-organelle communication and highlights potential diagnostic and therapeutic opportunities to mitigate ovarian functional decline. Together, this perspective provides a mitochondria-centric paradigm for understanding ovarian aging and guiding strategies to preserve female reproductive longevity.