The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

This review focuses on problems of the intracellular regulation of mitochondrial function in the brain via the (i) supply of mitochondria with ADP by means of ADP shuttles and channels and (ii) the Ca2+ control of mitochondrial substrate supply. The permeability of the mitochondrial outer membrane for adenine nucleotides is low. Therefore rate dependent concentration gradients exist between the mitochondrial intermembrane space and the cytosol. The existence of dynamic ADP gradients is an important precondition for the functioning of ADP shuttles, for example CrP-shuttle. Cr at mM concentrations instead of ADP diffuses from the cytosol through the porin pores into the intermembrane space. The CrP-shuttle isoenzymes work in different directions which requires different metabolite concentrations mainly caused by dynamic ADP compartmentation. The ADP shuttle mechanisms alone cannot explain the load dependent changes in mitochondrial energization, and a complete model of mitochondrial regulation have to account the Ca2+-dependent substrate supply too. According to the old paradigmatic view, Ca2+cyt taken up by the mitochondrial Ca2+ uniporter activates dehydrogenases within the matrix. However, recently it was found that Ca2+cyt at low nM concentrations exclusively activates the state 3 respiration via aralar, the mitochondrial glutamate/aspartate carrier. At higher Ca2+cyt (> 500 nM), brain mitochondria take up Ca2+ for activation of substrate oxidation rates. Since brain mitochondrial pyruvate oxidation is only slightly influenced by Ca2+cyt, it was proposed that the cytosolic formation of pyruvate from its precursors is tightly controlled by the Ca2+dependent malate/aspartate shuttle. At low (50100 nM) Ca2+cyt the pyruvate formation is suppressed, providing a substrate limitation control in neurons. This so called gas pedal mechanism explains why the energy metabolism of neurons in the nucleus suprachiasmaticus could be down-regulated at night but activated at day as a basis for the circadian changes in Ca2+cyt. It also could explain the energetic disadvantages caused by altered Ca2+cyt at mitochondrial diseases and neurodegeneration. (c) 2013 IUBMB Life, 65(3):180190, 2013