title: Inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina.
abstract: Transport of pyruvate into mitochondria by the mitochondrial pyruvate carrier is crucial for complete oxidation of glucose and for biosynthesis of amino acids and lipids. Zaprinast is a well known phosphodiesterase inhibitor and lead compound for sildenafil. We found Zaprinast alters the metabolomic profile of mitochondrial intermediates and amino acids in retina and brain. This metabolic effect of Zaprinast does not depend on inhibition of phosphodiesterase activity. By providing (13)C-labeled glucose and glutamine as fuels, we found that the metabolic profile of the Zaprinast effect is nearly identical to that of inhibitors of the mitochondrial pyruvate carrier. Both stimulate oxidation of glutamate and massive accumulation of aspartate. Moreover, Zaprinast inhibits pyruvate-driven O2 consumption in brain mitochondria and blocks mitochondrial pyruvate carrier in liver mitochondria. Inactivation of the aspartate glutamate carrier in retina does not attenuate the metabolic effect of Zaprinast. Our results show that Zaprinast is a potent inhibitor of mitochondrial pyruvate carrier activity, and this action causes aspartate to accumulate at the expense of glutamate. Our findings show that Zaprinast is a specific mitochondrial pyruvate carrier (MPC) inhibitor and may help to elucidate the roles of MPC in amino acid metabolism and hypoglycemia.
authors.affiliation: From the Department of Biochemistry.
authors.forename: Jianhai
authors.initials: J
authors.lastname: Du
authors.forename: Whitney M
authors.initials: WM
authors.lastname: Cleghorn
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras
authors.forename: Ken
authors.initials: K
authors.lastname: Lindsay
authors.forename: Austin M
authors.initials: AM
authors.lastname: Rountree
authors.forename: Andrei O
authors.initials: AO
authors.lastname: Chertov
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Turner
authors.forename: Ayse
authors.initials: A
authors.lastname: Sahaboglu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Linton
authors.forename: Martin
authors.initials: M
authors.lastname: Sadilek
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
authors.forename: Ian R
authors.initials: IR
authors.lastname: Sweet
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: James B
authors.initials: JB
authors.lastname: Hurley
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000166:cytology; D002952:Citric Acid Cycle / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D011688:Purinones / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000378:metabolism*; D012160:Retina / Q000166:cytology*
chemical_list: D011688:Purinones; D001224:Aspartic Acid; D018698:Glutamic Acid; D019289:Pyruvic Acid; C011145:zaprinast; D010100:Oxygen
keywords: Aspartate; Glutamate; Metabolism; Phosphodiesterases; Pyruvate; Retina