<p>Mitochondria-associated endoplasmic reticulum membranes (MAMs) constitute highly dynamic signaling hubs that coordinate a spatiotemporal network regulating calcium flux, lipid trafficking, and innate immune activation. Beyond functioning as physical organelle tethers, the plasticity of MAMs is essential for cellular resilience. Notably, maladaptive remodeling of these contacts, which presents a spatiotemporal paradox in that both pathological tightening and excessive dissociation can precipitate dysfunction, underlies the pathogenesis of diverse complex diseases, including neurodegeneration, cardiovascular failure, and kidney injury. In this review, we provide an integrated synthesis of the molecular architecture of MAMs and highlight the indispensable role of endoplasmic reticulum (ER)–mitochondria coupling in sustaining physiological homeostasis. We further dissect how MAM dysregulation operates as a central convergence point for metabolic stress and inflammatory signaling. Additionally, we summarize technological advances such as super-resolution imaging and multi-omics frameworks that increasingly resolve the structural and functional heterogeneity of MAMs. Importantly, emerging evidence indicates a therapeutic paradigm shift: several widely used clinical agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors and metformin, appear to exert their renoprotective and metabolic benefits by restoring or stabilizing MAM integrity. Together, these insights reposition MAMs not as passive structural bystanders but as actionable, high-value therapeutic targets for next-generation precision medicine and drug repurposing strategies.</p> Graphical Abstract <p></p>