Mitochondrial dysfunction drives cellular senescence: Molecular mechanisms of inter-organelle communication.

Abstract

Mitochondrial dysfunction is a central driver of cellular senescence, a core hallmark of aging. While intrinsic mechanisms have been extensively reviewed, this article offers a novel paradigm by emphasizing the critical role of interorganellar communication in mitochondria-mediated senescence. We present a systematic dissection of the molecular mechanisms underlying functional crosstalk between mitochondria and key organelles, including the endoplasmic reticulum (ER), lysosomes, and peroxisomes. A particular focus is placed on established regulatory hubs such as mitochondria-associated ER membranes (MAMs), which orchestrate calcium signaling, lipid metabolism, and inflammatory responses. We further explore emerging pathways involving lysosomal mitochondrial coordination in nutrient sensing and mitophagy, and peroxisomal mitochondrial cooperation in redox balance and lipid homeostasis. By elucidating how defects in these dynamic networks propagate mitochondrial damage and execute senescence, this review establishes a unified framework for aging as integrated organelle network dysfunction. This synthesis advances fundamental aging biology and identifies novel molecular targets, providing a foundation for developing therapeutic strategies targeting organelle networks against age related pathologies.