Pyruvate Transport and Metabolism in the Central Nervous System

Abstract

We review the transport and enzyme systems involved in cerebral ­pyruvate metabolism, combining the information derived from recent genome sequencing technologies and in vivo or in vitro 13C and (13C, 2H) NMR approaches. Emphasis is placed on the role of subcellular compartmentation in the metabolic coupling between neurons and glial cells during glutamatergic neurotransmission. Proton-linked monocarboxylate transport through the plasma membrane utilizes the monocarboxylate transporters MCT as coded by the family of SLC16 genes, of which MCT4 and MCT2 are found in astrocytes and neurons, respectively. Cytosolic metabolism of monocarboxylates is kinetically compartmented in neurons and astrocytes with two different pyruvate pools originated from extracellular glucose or monocarboxylates, respectively. Mitochondrial transport of pyruvate is mediated by the pyruvate carrier PyC, a member of the mitochondrial carrier proteins, coded by the SLC25 gene family. Intramitochondrial oxidation of pyruvate in the cerebral tricarboxylic acid cycle is mainly controlled by pyruvate dehydrogenase, an ubiquitous multienzyme complex. Pyruvate carboxylase, an exclusively astrocytic enzyme, plays a fundamental anaplerotic role replenishing the glutamate and GABA pools involved in neurotransmission. Recent results obtained with cerebral mitochondria, primary cultures of neurons and astrocytes or in the in vivo brain with (13C,2H) NMR have revealed the presence of two kinetically different glutamate pools in neurons and astrocytes. The subcellular compartmentation of glutamate and pyruvate were not considered in previous interpretations of metabolic coupling between neurons and glial cells in vivo. To account for these findings we proposed a novel redox coupling mechanism incorporating intracellular glutamate and monocarboxylate compartmentation. Transcellular redox coupling is based on: (a) the intracellular coupling of glycolysis and oxidation in neurons and astrocytes through NAD(P)/NAD(P)H redox switches, (b) the transcellular coupling of NAD(P)/NAD(P)H redox states in neurons and glial cells through the intercellular exchange of monocarboxylate reducing equivalents and (c) the glutamate-glutamine cycle, exchanging only the cytosolic (or vesicular) pools of glutamate and glutamine in both neural cells.