Ca2 + regulation of mitochondrial function in neurons

Abstract

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 S0.5 for Ca2+ of 300nM and 3.4μM, 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+-depolarization, 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.