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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月16日

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  • Satinder Kaur,
  • Gurjit Kaur Bhatti,
  • Naina Khullar,
  • Inderpal Singh Sidhu,
  • Umashanker Navik,
  • Jasvinder Singh Bhatti

摘要

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.