Role of mitochondria-associated endoplasmic reticulum membranes in hepatic ischemia-reperfusion injury: Molecular architecture, pathological remodeling, and therapeutic prospects.

Abstract

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic platforms that integrate calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, and oxidative stress. In hepatic ischemia-reperfusion injury (HIRI), MAMs act as a structural-functional hub that amplifies the cascade from ischemic stress to reperfusion injury. In this review, we analyze the main tethering networks of MAMs and their pathological remodeling in HIRI, such as the uncoupling of the structure, opening of the mitochondrial permeability transition pore (mPTP) induced by Ca2 + overload, aggravation of endoplasmic reticulum (ER) stress, defective mitophagy, and a vicious loop of reactive oxygen species (ROS)/lipid peroxidation. Direct molecular and interventional evidence has proved the causal link between dysfunction of MAMs and the progression of HIRI. The state of MAMs determines whether hepatocytes undergo repair or irreversible injury. Based on these insights, a novel clinical strategy is proposed: targeting MAMs through a multi-level framework of "structural stabilization-calcium modulation-mitophagy restoration," delivered during perioperative windows such as organ preservation and machine perfusion. This framework elevates MAMs from a mechanistic concept to a monitorable, stratifiable, and actionable therapeutic node, offering a translational direction for protecting high-risk and marginal liver grafts in transplantation and hepatectomy.