Mitochondrial Calcium Handling in Physiology and Disease

Calcium (Ca²⁺) accumulation inside mitochondria represents a pleiotropic signal controlling a wide range of cellular functions, including key metabolic pathways and life/death decisions. This phenomenon has been first described in the 1960s, but the identity of the molecules controlling this process remained a mystery until just few years ago, when both mitochondrial Ca²⁺ uptake and release systems were genetically dissected. This finally opened the possibility to develop genetic models to directly test the contribution of mitochondrial Ca²⁺ homeostasis to cellular functions. Here we summarize our current understanding of the molecular machinery that controls mitochondrial Ca²⁺ handling and critically evaluate the physiopathological role of mitochondrial Ca²⁺ signaling, based on recent evidences obtained through in vitro and in vivo models.