Mitochondrial Ca(2+) Signaling in Health, Disease and Therapy

The divalent cation calcium (Ca(2+)) is considered one of the main second messengers inside cells and acts as the most prominent signal in a plethora of biological processes. Its homeostasis is guaranteed by an intricate and complex system of channels, pumps, and exchangers. In this context, by regulating cellular Ca(2+) levels, mitochondria control both the uptake and release of Ca(2+). Therefore, at the mitochondrial level, Ca(2+) plays a dual role, participating in both vital physiological processes (ATP production and regulation of mitochondrial metabolism) and pathophysiological processes (cell death, cancer progression and metastasis). Hence, it is not surprising that alterations in mitochondrial Ca(2+) (mCa(2+)) pathways or mutations in Ca(2+) transporters affect the activities and functions of the entire cell. Indeed, it is widely recognized that dysregulation of mCa(2+) signaling leads to various pathological scenarios, including cancer, neurological defects and cardiovascular diseases (CVDs). This review summarizes the current knowledge on the regulation of mCa(2+) homeostasis, the related mechanisms and the significance of this regulation in physiology and human diseases. We also highlight strategies aimed at remedying mCa(2+) dysregulation as promising therapeutical approaches.