title: A mitochondrial CO2-adenylyl cyclase-cAMP signalosome controls yeast normoxic cytochrome c oxidase activity.
abstract: Mitochondria, the major source of cellular energy in the form of ATP, respond to changes in substrate availability and bioenergetic demands by employing rapid, short-term, metabolic adaptation mechanisms, such as phosphorylation-dependent protein regulation. In mammalian cells, an intramitochondrial CO2-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway regulates aerobic energy production. One target of this pathway involves phosphorylation of cytochrome c oxidase (COX) subunit 4-isoform 1 (COX4i1), which modulates COX allosteric regulation by ATP. However, the role of the CO2-sAC-cAMP-PKA signalosome in regulating COX activity and mitochondrial metabolism and its evolutionary conservation remain to be fully established. We show that in Saccharomyces cerevisiae, normoxic COX activity measured in the presence of ATP is 55% lower than in the presence of ADP. Moreover, the adenylyl cyclase Cyr1 activity is present in mitochondria, and it contributes to the ATP-mediated regulation of COX through the normoxic subunit Cox5a, homologue of human COX4i1, in a bicarbonate-sensitive manner. Furthermore, we have identified 2 phosphorylation targets in Cox5a (T65 and S43) that modulate its allosteric regulation by ATP. These residues are not conserved in the Cox5b-containing hypoxic enzyme, which is not regulated by ATP. We conclude that across evolution, a CO2-sAC-cAMP-PKA axis regulates normoxic COX activity.
authors.affiliation: Department of Pharmacology and.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Hess
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, USA;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.affiliation: School of Biosciences, University of Kent, Canterbury, Kent, UK.
authors.forename: Fritz A
authors.initials: FA
authors.lastname: Mühlschlegel
authors.affiliation: Department of Pharmacology and.
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
authors.affiliation: Department of Pharmacology and.
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA; and abarrientos@med.miami.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Barrientos
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D002245:Carbon Dioxide / Q000378:metabolism; D015687:Cell Hypoxia; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C114727:RRF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D002245:Carbon Dioxide; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; C530066:Cox5a protein, S cerevisiae; C530067:Cox5b protein, S cerevisiae; D003576:Electron Transport Complex IV; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Cyr1; hypoxic Cox5b; mitochondrial energy metabolism; normoxic Cox5a