Neither too much nor too little: mitochondrial calcium concentration as a balance between physiological and pathological conditions.

Ca ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca homeostasis since mitochondrial Ca (mitCa) is a key regulator of oxidative metabolism and cell death. MitCa uptake is mediated by the mitochondrial Ca uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, "Dosis sola facit venenum,"in pathological conditions, mitCa overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa in physiopathological processes.