Dynamic imbalance of mitochondria-associated ER membranes in cardiovascular disease: mechanisms, context dependence and therapeutic potential

Abstract

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic contact sites that coordinate structural and functional communication between the endoplasmic reticulum (ER) and mitochondria. By organizing tethering complexes, calcium channels, lipid-transfer machinery, and stress-responsive signaling modules, MAMs regulate Ca2+ homeostasis, lipid metabolism, mitochondrial dynamics, mitophagy, oxidative stress, endoplasmic reticulum stress, and cell fate determination. Increasing evidence indicates that MAMs dysfunction is critically involved in the initiation and progression of cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, myocardial infarction, diabetic cardiomyopathy, dilated cardiomyopathy, and heart failure. In these settings, disrupted or excessive ER-mitochondria coupling can trigger mitochondrial Ca2+ overload, metabolic remodeling, reactive oxygen species accumulation, inflammatory activation, and programmed cell death. Conversely, preserved or appropriately remodeled MAMs integrity supports mitochondrial bioenergetics, adaptive stress responses, and cardiomyocyte or vascular cell survival. This review summarizes the molecular architecture and biological functions of major MAMs-associated complexes, and discusses their context-dependent roles in cardiovascular pathophysiology. We further highlight the therapeutic potential of targeting MAMs structure and function as a strategy to restore organelle homeostasis and improve cardiovascular outcomes.