Mitochondria-associated membranes in heart failure: from molecular mechanisms to therapeutic targets

Mitochondria-associated endoplasmic reticulum membranes (MAMs) serve as pivotal functional contact sites linking mitochondria and the endoplasmic reticulum, playing a role in orchestrating various cellular life activities, including calcium homeostasis, mitochondrial quality control, endoplasmic reticulum stress, lipid synthesis and transport, inflammation and innate immunity, apoptosis, autophagy, ferroptosis, and oxidative stress. Recent research has demonstrated that the structural and functional dysregulation of MAMs significantly contributes to the onset and progression of heart failure. This review systematically examined the molecular composition, structural features, and dynamic regulatory mechanisms of MAMs, emphasizing their central roles in the pathophysiological processes of heart failure, such as calcium homeostasis imbalance, mitochondrial dynamics disorders, endoplasmic reticulum stress, metabolic reprogramming, and inflammatory and immune responses. We proposed an in-depth analysis of the differential manifestations of MAMs across distinct heart failure phenotypes (HFrEF and HFpEF) and summarized potential therapeutic strategies targeting MAMs, along with the challenges encountered in their clinical translation. Finally, we proposed a novel research paradigm for MAMs based on multi-omics integration and artificial intelligence, offering a theoretical foundation for the development of precise treatment plans for heart failure.