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

Abstract

Mitochondria are pivotal hubs in maintaining cellular homeostasis, encompassing vital processes such as bioenergetics, redox regulation, Ca²⁺ signaling, and programmed cell death. Ca²⁺ 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 Ca²⁺ uptake and efflux. At the mitochondrial level, Ca²⁺ 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 Ca²⁺ (Ca²⁺_mito) levels influence cellular activity and functionality. The regulation of mitochondrial Ca²⁺ homeostasis involves the collaborative participation of the mitochondrial Ca²⁺ transporter and the mitochondria-endoplasmic reticulum contact sites (MERCS). This review provides a comprehensive overview of current knowledge regarding the regulation of mitochondrial Ca²⁺ 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 Ca²⁺ homeostasis and its regulators, such as novel drug delivery systems and specific calcium-modulating agents.