Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects.
Phosphorylation of respiratory chain components has emerged as a mode of regulation of mitochondrial energy metabolism, but its mechanisms are still largely unexplored. A recently discovered intramitochondrial signalling pathway links CO(2) generated by the Krebs cycle with the respiratory chain, through the action of a mitochondrial soluble adenylyl cyclase (mt-sAC). Cytochrome oxidase (COX), whose deficiency causes a number of fatal metabolic disorders, is a key mitochondrial enzyme activated by mt-sAC. We have now discovered that the mt-sAC pathway modulates mitochondrial biogenesis in a reactive oxygen species dependent manner, in cultured cells and in animals with COX deficiency. We show that upregulation of mt-sAC normalizes reactive oxygen species production and mitochondrial biogenesis, thereby restoring mitochondrial function. This is the first example of manipulation of a mitochondrial signalling pathway to achieve a direct positive modulation of COX, with clear implications for the development of novel approaches to treat mitochondrial diseases.
Acin-Perez
Rebeca
R
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA.
Salazar
Eric
E
Brosel
Sonja
S
Yang
Hua
H
Schon
Eric A
EA
Manfredi
Giovanni
G
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000201:enzymology / Q000235:genetics; D009154:Mutation; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D003576:Electron Transport Complex IV; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases