High-Salt Diet Disrupts Mitochondria-Associated Endoplasmic Reticulum Membrane: A Unifying Mechanism Linking Nutrition to Systemic Pathologies.

The mitochondrial-associated endoplasmic reticulum membrane (MAM) is a dynamic contact site formed through protein-mediated connections between the endoplasmic reticulum (ER) and outer mitochondrial membrane. As a pivotal signaling and metabolic hub, MAM regulates core cellular physiological processes, including calcium homeostasis, lipid biosynthesis and trafficking, mitochondrial dynamics, autophagy, apoptosis, and inflammasome formation and activation. Growing evidence indicates that the disruption of MAM integrity and function is closely associated with various disorders induced by excessive salt consumption. High salt intake perturbs ER-mitochondrial calcium ion exchange, partly through elevated intracellular sodium concentrations, leading to the structural and functional impairment of MAM. This disruption of calcium homeostasis subsequently triggers the ER and oxidative stress responses, exacerbating cellular damage. Concurrently, high-salt diets interfere with MAM-mediated lipid synthesis and transport, contributing to mitochondrial dysfunction and accelerating disease development. This review summarizes the involvement and underlying molecular mechanisms of MAM in high-salt diet-related disorders including hypertension, cardiovascular disease, obesity, and metabolic dysfunction-associated fatty liver disease. Furthermore, this review explores the translational potential of targeting MAM as a therapeutic intervention, providing novel insights for developing interventions that target inter-organelle communication to combat salt-related systemic disorders.