Decoding the influence of mitochondrial Ca2+ regulation on neurodegenerative disease progression

Mitochondria are pivotal hubs in maintaining cellular homeostasis, encompassing vital processes such as bioenergetics, redox regulation, Ca 2+ signaling, and programmed cell death. Ca 2+ is a key second messenger within cells, paramount in numerous critical biological processes. The maintenance of mitochondrial calcium homeostasis relies on a delicate balance between Ca 2+ uptake and efflux. At the mitochondrial level, Ca 2+ serves a dual function, participating in essential physiological processes such as ATP production and the regulation of mitochondrial metabolisms and contributing to pathophysiological events, including cell death and cancer metastasis. Alterations in mitochondrial Ca 2+ (Ca 2+ mito ) levels influence cellular activity and functionality. The regulation of mitochondrial Ca 2+ homeostasis involves the collaborative participation of the mitochondrial Ca 2+ transporter and the mitochondria-endoplasmic reticulum contact sites (MERCS). This review provides a comprehensive overview of current knowledge regarding the regulation of mitochondrial Ca 2+ homeostasis and its implications in both physiological processes and neurodegenerative disorders. Moreover, we highlight potential opportunities and challenges in developing therapeutic interventions that target mitochondrial Ca 2+ homeostasis and its regulators, such as novel drug delivery systems and specific calcium-modulating agents. • Mitochondrial calcium homeostasis depends on the dynamic balance of mitochondrial Ca 2+ uptake and efflux. • Mitochondrial calcium homeostasis orchestrates neuronal energy production through intricate local regulatory mechanisms. • Targeting mitochondrial Ca 2+ regulation holds promise as a potential preventive strategy for a variety of neurodegenerative diseases. • The development of drugs that selectively activate or inhibit components of the MCU complex, NCLX, and MERCS is crucial for precisely targeting mitochondrial Ca 2+ homeostasis in the treatment of neurodegenerative diseases.