MAMs-Mediated Calcium Homeostasis in the Pathophysiology of Cardiovascular Diseases: A Mini-Review
Abstract
Abstract Cardiovascular diseases (CVDs) remain a leading threat to human health, imposing substantial morbidity and a considerable clinical burden worldwide. Disrupted mitochondrial calcium ions (Ca2⁺) homeostasis is increasingly recognized as a shared pathophysiological feature of diverse CVDs. Mitochondria and the endoplasmic reticulum (ER) are key organelles involved in intracellular Ca2⁺ homeostasis and energy metabolism, and their physical and functional coupling occurs at mitochondria-associated ER membranes (MAMs). Through protein complexes such as IP3R–GRP75–VDAC1, VAPB–PTPIP51 and MFN1–MFN2, MAMs coordinate a finely tuned Ca2⁺-signalling network that is essential for maintaining mitochondrial Ca2⁺ homeostasis. This review provides a systematic overview of the structural organization of MAMs and the molecular mechanisms governing MAM-mediated Ca2⁺ transfer, with particular emphasis on how dysregulated Ca2⁺ signalling at MAMs contributes to myocardial ischaemia–reperfusion injury, atherosclerosis, heart failure (HF), pulmonary arterial hypertension and diabetic cardiomyopathy. Furthermore, on this basis, this review focuses on the IP3Rs‑GRP75‑VDAC1 complex, mitochondrial calcium uniporter (MCU)‑associated calcium‑transport pathways, the endoplasmic reticulum stress‑MAMs‑mitochondrial calcium overload axis, as well as MAMs‑mediated signaling cascades, and systematically elaborates the latest research advances of therapeutic interventions including small‑molecule inhibitors, targeted peptides, calcium chelators, chemical chaperones and natural products. At present, available therapeutic evidence is mostly obtained from cellular and animal models. The process of clinical translation is still constrained by suboptimal target selectivity, dilemmas in bidirectional calcium‑signal regulation, bottlenecks in tissue‑specific delivery and the lack of long‑term safety evaluation. This review is expected to provide theoretical foundations and cutting‑edge insights for novel cardiovascular drug discovery and translational research targeting MAMs‑related calcium homeostasis.