Mitochondria-ER contact sites (MERCS) in the cell cycle: molecular architecture and functional remodeling across cellular states

Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are nanoscopic, dynamic platforms integrating metabolism, signaling, and stress responses to regulate cell fate. These nanoscopic interfaces remodel continuously to meet the demands of proliferating, quiescent, and senescent cells. We synthesize evidence that MERCS actively coordinate local Ca²⁺ signaling, non-vesicular lipid transfer, and proteostasis to shape mitochondrial function and cellular homeostasis. We discuss how MERCS architecture changes across the cell cycle and during arrest, distinguishing adaptive from maladaptive remodeling, and consider therapeutic potential in aging and age-related disease.