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: Anna Signorile, Arcangela Santeramo, Grazia Tamma, Tommaso Pellegrino, Susanna D'Oria, Paolo Lattanzio, Domenico De Rasmo
• Journal: Biochimica et biophysica acta. Molecular cell research (Biochim Biophys Acta Mol Cell Res) Vol. 1864 Issue 2 Pg. 355-366 (Feb 2017) ISSN: 0167-4889 [Print] Netherlands
• PMID: 27890624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Reactive Oxygen Species
• SIRT3 protein, rat
• tert-Butylhydroperoxide
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Sirtuins

Topics

• Animals
• Apoptosis
• Cell Line
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Cytosol (metabolism)
• Fluorescence Resonance Energy Transfer
• Mitochondria, Heart (drug effects, metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Sirtuins (metabolism)
• tert-Butylhydroperoxide (pharmacology)