Mitochondria are critical for cellular homeostasis, regulating bioenergetics, redox balance, Ca2+ signaling, and cell death. Mitochondrial Ca2+ (Ca2+mito) plays a dual role in physiological processes like ATP production and pathophysiological events, including cell death and cancer. The balance of Ca2+ uptake and efflux, mediated by mitochondrial transporters and mitochondria-endoplasmic reticulum contact sites (MERCS), is essential for maintaining Ca2+mito homeostasis. This review summarizes current insights into mitochondrial Ca2+ regulation, its roles in physiology and neurodegenerative diseases, and explores therapeutic strategies targeting Ca2+ homeostasis, including innovative drug delivery systems and calcium-modulating agents. 

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