title: Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation.
abstract: Mitochondria constantly respond to changes in substrate availability and energy utilization to maintain cellular ATP supplies, and at the same time control reactive oxygen radical (ROS) production. Reversible phosphorylation of mitochondrial proteins has been proposed to play a fundamental role in metabolic homeostasis, but very little is known about the signaling pathways involved. We show here that protein kinase A (PKA) regulates ATP production by phosphorylation of mitochondrial proteins, including subunits of cytochrome c oxidase. The cyclic AMP (cAMP), which activates mitochondrial PKA, does not originate from cytoplasmic sources but is generated within mitochondria by the carbon dioxide/bicarbonate-regulated soluble adenylyl cyclase (sAC) in response to metabolically generated carbon dioxide. We demonstrate for the first time the existence of a CO(2)-HCO(3)(-)-sAC-cAMP-PKA (mito-sAC) signaling cascade wholly contained within mitochondria, which serves as a metabolic sensor modulating ATP generation and ROS production in response to nutrient availability.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Acin-Perez
authors.forename: Eric
authors.initials: E
authors.lastname: Salazar
authors.forename: Margarita
authors.initials: M
authors.lastname: Kamenetsky
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D002245:Carbon Dioxide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases