Mitochondrial calcium homeostasis and implications for human health.

Ca2+ has a central role in all the cellular functions. Its signal is shaped by the coordinated action of the Ca2+ transporting proteins and the intracellular organelles. Mitochondria have a special role since they are the energy powerhouse of the cells, but also a major hub for cellular Ca2+ signaling crucial for cell life and death. The mitochondrial membrane potential generated by the respiratory chain is used by the ATP synthase for running the endergonic reaction of ADP phosphorylation and by the mitochondrial Ca2+ uniporter to take up Ca2+ into the matrix accordingly its electrochemical gradient. The action of the H+/Ca2+ and the Na+/Ca2+ exchangers prevents the attainment of the electrical equilibrium. Impaired Ca2+ handling can lead to matrix Ca2+ overload and activation of the high conductance mitochondrial permeability transition pore. Mitochondrial Ca2+ overload has deleterious consequences for the cells: increased membrane permeability leads to the release of pro-apoptotic factors and the activation of the apoptotic pathway. Even the absence of proper Ca2+ transfer from the endoplasmic reticulum to mitochondria could be detrimental since it results in defective metabolism and autophagy. Thus, mitochondrial Ca2+ handling dysfunctions may have important implications in different physio-pathological conditions.