CALCIUM SIGNALING IN MITOCHONDRIA: METABOLIC CONTROL AND MITOCHONDRIAL PHYSIOPATHOLOGY

Ca2+ entry in mitochondria through the Ca2+ uniporter (CaU) is important in cell Ca2+ signaling, but its persistence in mitochondria is associated with mitochondrial dysfunction and cell death. We are interested in the study of systems for Ca2+ signaling in mitochondria that do not require Ca2+ entry in the organelle, the mitochondrial carriers of aspartate-glutamate carriers (AGC) aralar and citrin, and of ATP-Mg/Pi, or Short CaMCs (SCaMCs). Both AGCs and SCaMCs have calcium binding domains facing the intermembrane space which are activated by Ca2+ without the need of calcium entry in mitochondria. Aralar and citrin, the brain and liver AGCs, are components of the malate-aspartate NADH shuttle. We have shown that both AGC isoforms are regulated by Ca2+ at concentrations lower than those required to activate CaU and are essential to transmit very small Ca2+ signals to brain or beta-cell mitochondria. On the other hand, Ca2+ concentrations activating SCaMCs are close to those activating