Ca2+ regulation of mitochondrial function in neurons

Calcium is thought to regulate respiration but it is unclear whether this is dependent on the increase in ATP demand caused by any Ca2+ signal or to Ca2+ itself. [Na+](i), [Ca2+](i) and [ATP](i) dynamics in intact neurons exposed to different workloads in the absence and presence of Ca2+ clearly showed that Ca2+-stimulation of coupled respiration is required to maintain [ATP](i) levels. Ca2+ may regulate respiration by activating metabolite transport in mitochondria from outer face of the inner mitochondrial membrane, or after Ca2+ entry in mitochondria through the calcium uniporter (MCU). Two Ca2+-regulated mitochondrial metabolite transporters are expressed in neurons, the aspartate glutamate exchanger ARALAR/AGC1/Slc25a12, a component of the malate aspartate shuttle, and the ATP-Mg/Pi exchanger SCaMC-3/APC2/Slc25a23, with S-0.5 for Ca2+ of 300 nM and 3.4 mu M, respectively. The lack of SCaMC-3 results in a smaller Ca2+-dependent stimulation of respiration only at high workloads, as caused by veratridine, whereas the lack of ARALAR reduced by 46% basal OCR in intact neurons using glucose as energy source and the Ca2+-dependent responses to all workloads: a reduction of about 65-70% in the response to the high workload imposed by veratridine, and completely suppression of the OCR responses to moderate (K+-depolarization) and small (carbachol) workloads, effects reverted by pyruvate supply. For K+-epolarization, this occurs in spite of the presence of large [Ca2+](mit) signals and increased formation of mitochondrial NAD(P)H. These results show that ARALAR-MAS is a major contributor of Ca2+-stimulated respiration in neurons by providing increased pyruvate supply to mitochondria. In its absence and under moderate workloads, matrix Ca2+ is unable to stimulate pyruvate metabolism and entry in mitochondria suggesting a limited role of MCU in these conditions. This article was invited for a Special Issue entitled: 18th European Bioenergetic Conference. (C) 2014 Elsevier B.V. All rights reserved.