Ivanenko Sergey¹, Nakamura Emi², Tariq Laiba³, Silva Rui⁴, Schubert Lennart⁵, Blanchet Inès⁶
ABSTRACT:
Background: Calcium (Ca²⁺) signaling serves as a ubiquitous and tightly regulated second messenger system that coordinates a vast array of cellular functions, including energy metabolism, gene expression, and programmed cell death. Through spatial and temporal modulation of intracellular Ca²⁺ fluxes, cells integrate diverse physiological signals and maintain homeostasis. Perturbations in calcium homeostasis are intimately linked to metabolic dysregulation, mitochondrial dysfunction, and apoptosis, positioning calcium as a central node in health and disease. Methods and Results: This review presents a comprehensive biochemical framework outlining the molecular pathways and organelle crosstalk underlying calcium-dependent regulation of metabolism and apoptosis. Ca²⁺ influx through plasma membrane channels (e.g., voltage-gated calcium channels, TRP channels) and release from intracellular stores (e.g., ER via IP₃ and ryanodine receptors) shape cytosolic Ca²⁺ transients that activate calmodulin, calcineurin, CaMKs, and other calcium-sensitive enzymes. Mitochondrial calcium uptake via the mitochondrial calcium uniporter (MCU) stimulates oxidative phosphorylation by enhancing the activity of key dehydrogenases in the TCA cycle. However, Ca²⁺ overload promotes mitochondrial permeability transition pore (mPTP) opening, leading to cytochrome c release and caspase activation. At the ER–mitochondria interface, known as mitochondria-associated membranes (MAMs), calcium signaling orchestrates metabolic efficiency and stress responses. Dysregulated calcium dynamics contribute to a range of pathologies including neurodegeneration, diabetes, and cancer by disrupting ATP production and triggering intrinsic apoptotic pathways. Pharmacological agents that modulate calcium fluxes or buffer intracellular calcium are being explored to restore metabolic balance and prevent unwanted cell death. Conclusion: Calcium signaling operates as a finely tuned biochemical system that interlinks metabolic regulation and apoptotic signaling.