Mitochondrial Transporters as Novel Targets for Intracellular Calcium Signaling

Abstract

Ca2+signaling in mitochondria is important to tune mitochondrial function to a variety of extracellular stimuli. The main mechanism is Ca2+entry in mitochondria via the Ca2+uniporter followed by Ca2+activation of three dehydrogenases in the mitochondrial matrix. This results in increases in mitochondrial NADH/NAD ratios and ATP levels and increased substrate uptake by mitochondria. We review evidence gathered more than 20 years ago and recent work indicating that substrate uptake, mitochondrial NADH/NAD ratios, and ATP levels may be also activated in response to cytosolic Ca2+signals via a mechanism that does not require the entry of Ca2+in mitochondria, a mechanism depending on the activity of Ca2+-dependent mitochondrial carriers (CaMC). CaMCs fall into two groups, the aspartate-glutamate carriers (AGC) and the ATP-Mg/Picarriers, also named SCaMC (for short CaMC). The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle, and citrin, the liver AGC, is also a member of the urea cycle. Both types of CaMCs are activated by Ca2+in the intermembrane space and function together with the Ca2+uniporter in decoding the Ca2+signal into a mitochondrial response.