title: Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain.
abstract: In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of "in vitro" produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and H89, an inhibitor of PKA.
authors.affiliation: Institute of Biomembrane and Bioenergetics, CNR, Bari 70124, Italy. Electronic address: d.derasmo@ibbe.cnr.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: De Rasmo
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Signorile
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Santeramo
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Larizza
authors.affiliation: Institute of Biomembrane and Bioenergetics, CNR, Bari 70124, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lattanzio
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Capitanio
authors.affiliation: Institute of Biomembrane and Bioenergetics, CNR, Bari 70124, Italy; Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Papa
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D042967:Electron Transport Complex I / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism
chemical_list: D007976:Leupeptins; D009842:Oligopeptides; D011480:Protease Inhibitors; D021122:Protein Subunits; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; C579271:ADCY10 protein, human; D000262:Adenylyl Cyclases; D042967:Electron Transport Complex I; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin
keywords: Mitochondria; Mitochondrial proteases; Respiratory complex I; Soluble adenylyl cyclase; cAMP/PKA signaling