title: Fluctuations in Cytosolic Calcium Regulate the Neuronal Malate-Aspartate NADH Shuttle: Implications for Neuronal Energy Metabolism.
abstract: The malate-aspartate NADH shuttle (MAS) operates in neurons and other cells to translocate reducing equivalents from the cytosol to the mitochondrial matrix, thus allowing a continued flux through the glycolytic pathway and metabolism of extracellular lactate. Recent discoveries have taught us that MAS is regulated by fluctuations in cytosolic Ca(2+) levels, and that this regulation is required to maintain a tight coupling between neuronal activity and mitochondrial respiration and oxidative phosphorylation. At cytosolic Ca(2+) fluctuations below the threshold of the mitochondrial calcium uniporter, there is a positive correlation between Ca(2+) and MAS activity; however, if cytosolic Ca(2+) increases above the threshold, MAS activity is thought to be reduced by an intricate mechanism. The latter forces the neurons to partly rely on anaerobic glycolysis producing lactate that may be metabolized subsequently, by neurons or other cells. In this review, we will discuss the evidence for Ca(2+)-mediated regulation of MAS that have been uncovered over the last decade or so, together with the need for further verification, and examine the metabolic ramifications for neurons.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049, Madrid, Spain. jsatrustegui@cbm.csic.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras, 28049, Madrid, Spain. jsatrustegui@cbm.csic.es.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28040, Madrid, Spain. jsatrustegui@cbm.csic.es.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark. laba@sund.ku.dk.
authors.forename: Lasse K
authors.initials: LK
authors.lastname: Bak
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008293:Malates / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
chemical_list: D008293:Malates; D009243:NAD; D001224:Aspartic Acid; D019344:Lactic Acid
keywords: Calcium; Malate–aspartate NADH shuttle; Metabolism; Mitochondria; Neuron