Calcium signalling and organelle crosstalk in cardiovascular disease: an interplay of cardiac cell death pathways.

Calcium (Ca²⁺), a fundamental intracellular second messenger, plays a pivotal role in cardiovascular physiology and pathology. While tightly regulated under normal conditions, Ca²⁺ homeostasis becomes profoundly dysregulated during myocardial infarction (MI), heart failure, ischemia-reperfusion injury, cardiac hypertrophy, and atherosclerosis, resulting in pathological signaling, organellar stress, and cardiomyocyte death. This review presents a comprehensive exploration of how intracellular Ca²⁺ orchestrates excitation-contraction coupling, mitochondrial energetics, sarcoplasmic reticulum (SR) buffering, and lysosomal signaling, while simultaneously modulating apoptosis, necrosis, pyroptosis, ferroptosis, and Clockophagy. We highlight the role of Ca²⁺ in the pathogenesis of atherosclerosis, vascular calcification, endothelial dysfunction, platelet activation, and fibroblast trans differentiation. In particular, we delineate how Ca²⁺ excitotoxicity extends across a range of organelles including mitochondria, the sarcoplasmic reticulum (SR), and lysosomes to mediate inter-organellar communication. This organellar communication, facilitated by Ca²⁺ signaling, drives the interplay of cardiac cell death mechanisms that culminate in cardiac tissue destruction. The involvement of TRPC channels in lysosome-SR-mitochondria crosstalk warrants further investigation to enable targeting of specific TRPC isoforms based on the type of cardiovascular disorder. Therapeutics targeting mitochondria-associated membranes (MAMs) and lysosomes simultaneously may offer a comprehensive and effective strategy for the treatment of cardiovascular disease.