Mechanisms and subcellular rewiring underlying the bidirectional structural remodeling of mitochondria-associated endoplasmic reticulum membranes in liver diseases

Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as subcellular signaling hubs that regulate hepatic metabolic homeostasis and cell fate.Across liver diseases, MAMs exhibit bidirectional structural remodeling, but the dominant pattern varies with disease context.In selected models, acute stress or early nutrient overload is associated with MAM over-coupling, mitochondrial Ca² + overload, and cell injury.In other metabolic settings, prolonged stress can be accompanied by abnormal MAM dissociation, impaired inter-organelle lipid transfer, and bioenergetic dysfunction.These bidirectional pathological features highlight the limitations of unidirectional intervention strategies.Therefore, this review examines bidirectional structural remodeling of MAMs across liver diseases, including metabolic dysfunction-associated steatotic liver disease, acute liver injury, liver fibrosis, and hepatocellular carcinoma.Furthermore, we evaluate whether the available evidence supports state-directed uncoupling or re-coupling in specific liver disease contexts.By comparing concordant and conflicting findings across disease stages, cell types, and experimental models, this review clarifies where the bidirectional framework is supported and where the evidence remains insufficient.