Mitochondria–Endoplasmic Reticulum Contact Sites in Cardiovascular Diseases: Molecular Mechanisms and Therapeutic Perspectives

Mitochondria–endoplasmic reticulum (ER) contact sites, frequently investigated as mitochondria-associated membranes (MAMs), coordinate calcium transfer, lipid exchange, proteostasis, and mitochondrial quality control. Their cardiovascular significance depends on whether local communication supports metabolic adaptation or amplifies injury. This narrative review integrates classical mechanisms with recent cardiovascular studies and adds an evidence-stratified appraisal of contact-site biology: human tissue observations are distinguished from animal and cellular experiments, and interventions with measured contact-site effects are separated from broader mitochondrial or ER-directed approaches. We examine myocardial ischemia/reperfusion injury, heart failure, atherosclerosis, pulmonary arterial hypertension, and selected additional cardiac stress settings. Particular attention is given to chaperone-dependent signaling, apoptosis-related regulation of ER calcium, cardiolipin metabolism, and the relationship between contact architecture and functional flux. Contrasting results indicate that contact number alone cannot define a beneficial or pathological state. Although experimental manipulation of contact-associated pathways can improve cardiovascular phenotypes, most therapeutic approaches remain preclinical, and multifunctional targets complicate attribution of benefit to MAMs. Major gaps include limited causal evidence in human myocardium, inconsistent structural measurements, incomplete separation of contact-specific functions, and insufficient long-term safety assessment. Progress requires disease- and stage-specific restoration of communication, supported by paired structural and functional measurements rather than generalized promotion or inhibition of organelle contacts.