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

Ca²⁺ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca²⁺ homeostasis since mitochondrial Ca²⁺ (mitCa²⁺) is a key regulator of oxidative metabolism and cell death. MitCa²⁺ uptake is mediated by the mitochondrial Ca²⁺ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa²⁺ 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, mitCa²⁺ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa²⁺ 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 mitCa²⁺ in physiopathological processes.