title: Mitochondrial cAMP prevents apoptosis modulating Sirt3 protein level and OPA1 processing in cardiac myoblast cells.
abstract: Mitochondria, responding to a wide variety of signals, including oxidative stress, are critical in regulating apoptosis that plays a key role in the pathogenesis of a variety of cardiovascular diseases. A number of mitochondrial proteins and pathways have been found to be involved in the mitochondrial dependent apoptosis mechanism, such as optic atrophy 1 (OPA1), sirtuin 3 (Sirt3), deacetylase enzyme and cAMP signal. In the present work we report a network among OPA1, Sirt3 and cAMP in ROS-dependent apoptosis. Rat myoblastic H9c2 cell lines, were treated with tert-butyl hydroperoxide (t-BHP) to induce oxidative stress-dependent apoptosis. FRET analysis revealed a selective decrease of mitochondrial cAMP in response to t-BHP treatment. This was associated with a decrease of Sirt3 protein level and proteolytic processing of OPA1. Pretreatment of cells with permeant analogous of cAMP (8-Br-cAMP) protected the cell from apoptosis preventing all these events. Using H89, inhibitor of the protein kinase A (PKA), and protease inhibitors, evidences have been obtained that ROS-dependent apoptosis is associated with an alteration of mitochondrial cAMP/PKA signal that causes degradation/proteolysis of Sirt3 that, in turn, promotes acetylation and proteolytic processing of OPA1.
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari 70124, Italy. Electronic address: anna.signorile@uniba.it.
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 Bioscience, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", Bari 70125, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Tamma
authors.affiliation: Department of Bioscience, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", Bari 70125, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pellegrino
authors.affiliation: Department of Biomedical Sciences and Human Oncology, University of Bari "Aldo Moro", Bari 70124, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: D'Oria
authors.affiliation: Institute of Biomembrane and Bioenergetics, CNR, Bari 70124, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Lattanzio
authors.affiliation: Institute of Biomembrane and Bioenergetics, CNR, Bari 70124, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: De Rasmo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; C000607791:SIRT3 protein, rat; D020122:tert-Butylhydroperoxide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D037761:Sirtuins
keywords: Apoptosis; Mitochondria; OPA1; Sirt3; cAMP