Oxidative stress induced mitochondrial protein kinase A mediates cytochrome c oxidase dysfunction
Previously we showed that Protein kinase A (PKA) activated in hypoxia and myocardial ischemia/reperfusion mediates phosphorylation of subunits I, IVi1 and Vb of cytochrome c oxidase. However, the mechanism of activation of the kinase under hypoxia remains unclear. It is also unclear if hypoxic stres...
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| creator | Srinivasan, Satish Spear, Joseph Chandran, Karunakaran Joseph, Joy Kalyanaraman, Balaraman Avadhani, Narayan G |
| description | Previously we showed that Protein kinase A (PKA) activated in hypoxia and myocardial ischemia/reperfusion mediates phosphorylation of subunits I, IVi1 and Vb of cytochrome c oxidase. However, the mechanism of activation of the kinase under hypoxia remains unclear. It is also unclear if hypoxic stress activated PKA is different from the cAMP dependent mitochondrial PKA activity reported under normal physiological conditions. In this study using RAW 264.7 macrophages and in vitro perfused mouse heart system we investigated the nature of PKA activated under hypoxia. Limited protease treatment and digitonin fractionation of intact mitochondria suggests that higher mitochondrial PKA activity under hypoxia is mainly due to increased sequestration of PKA Catalytic α (PKAα) subunit in the mitochondrial matrix compartment. The increase in PKA activity is independent of mitochondrial cAMP and is not inhibited by adenylate cyclase inhibitor, KH7. Instead, activation of hypoxia-induced PKA is dependent on reactive oxygen species (ROS). H89, an inhibitor of PKA activity and the antioxidant Mito-CP prevented loss of CcO activity in macrophages under hypoxia and in mouse heart under ischemia/reperfusion injury. Substitution of wild type subunit Vb of CcO with phosphorylation resistant S40A mutant subunit attenuated the loss of CcO activity and reduced ROS production. These results provide a compelling evidence for hypoxia induced phosphorylation as a signal for CcO dysfunction. The results also describe a novel mechanism of mitochondrial PKA activation which is independent of mitochondrial cAMP, but responsive to ROS. |
| doi_str_mv | 10.1371/journal.pone.0077129 |
| format | Article |
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However, the mechanism of activation of the kinase under hypoxia remains unclear. It is also unclear if hypoxic stress activated PKA is different from the cAMP dependent mitochondrial PKA activity reported under normal physiological conditions. In this study using RAW 264.7 macrophages and in vitro perfused mouse heart system we investigated the nature of PKA activated under hypoxia. Limited protease treatment and digitonin fractionation of intact mitochondria suggests that higher mitochondrial PKA activity under hypoxia is mainly due to increased sequestration of PKA Catalytic α (PKAα) subunit in the mitochondrial matrix compartment. The increase in PKA activity is independent of mitochondrial cAMP and is not inhibited by adenylate cyclase inhibitor, KH7. Instead, activation of hypoxia-induced PKA is dependent on reactive oxygen species (ROS). H89, an inhibitor of PKA activity and the antioxidant Mito-CP prevented loss of CcO activity in macrophages under hypoxia and in mouse heart under ischemia/reperfusion injury. Substitution of wild type subunit Vb of CcO with phosphorylation resistant S40A mutant subunit attenuated the loss of CcO activity and reduced ROS production. These results provide a compelling evidence for hypoxia induced phosphorylation as a signal for CcO dysfunction. The results also describe a novel mechanism of mitochondrial PKA activation which is independent of mitochondrial cAMP, but responsive to ROS.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0077129</identifier><identifier>PMID: 24130844</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Adenylate cyclase ; Animals ; Antioxidants ; Antioxidants - pharmacology ; Biology ; Biophysics ; Cardiology ; Catalysis ; Cell Hypoxia - drug effects ; Cell Line ; Cell Respiration - drug effects ; Cyclic adenosine monophosphate ; Cyclic AMP ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Cytochrome ; Cytochrome c ; Cytochrome oxidase ; Cytochrome-c oxidase ; Electron Transport Complex IV - genetics ; Electron Transport Complex IV - metabolism ; Endoplasmic reticulum ; Enzyme Activation - drug effects ; Enzymes ; Fractionation ; Free radicals ; Heart ; Hypoxia ; Inhibitors ; Ischemia ; Kinases ; Macrophages ; Mice ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - enzymology ; Mitochondria - metabolism ; Mutation ; Myocardial ischemia ; Myocardial Ischemia - enzymology ; Myocardial Ischemia - metabolism ; Myocardial Ischemia - pathology ; Oncology ; Oxidase ; Oxidative stress ; Oxidative Stress - drug effects ; Oxygen ; Phosphorylation ; Phosphorylation - drug effects ; Physiology ; Proteases ; Protein kinase A ; Protein kinases ; Protein Subunits - genetics ; Protein Subunits - metabolism ; Protein Transport - drug effects ; Proteins ; Proteolysis - drug effects ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Reperfusion ; Reperfusion Injury - enzymology ; Reperfusion Injury - metabolism ; Reperfusion Injury - pathology ; Rodents ; Veterinary colleges ; Veterinary medicine</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e77129-e77129</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Srinivasan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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However, the mechanism of activation of the kinase under hypoxia remains unclear. It is also unclear if hypoxic stress activated PKA is different from the cAMP dependent mitochondrial PKA activity reported under normal physiological conditions. In this study using RAW 264.7 macrophages and in vitro perfused mouse heart system we investigated the nature of PKA activated under hypoxia. Limited protease treatment and digitonin fractionation of intact mitochondria suggests that higher mitochondrial PKA activity under hypoxia is mainly due to increased sequestration of PKA Catalytic α (PKAα) subunit in the mitochondrial matrix compartment. The increase in PKA activity is independent of mitochondrial cAMP and is not inhibited by adenylate cyclase inhibitor, KH7. Instead, activation of hypoxia-induced PKA is dependent on reactive oxygen species (ROS). H89, an inhibitor of PKA activity and the antioxidant Mito-CP prevented loss of CcO activity in macrophages under hypoxia and in mouse heart under ischemia/reperfusion injury. Substitution of wild type subunit Vb of CcO with phosphorylation resistant S40A mutant subunit attenuated the loss of CcO activity and reduced ROS production. These results provide a compelling evidence for hypoxia induced phosphorylation as a signal for CcO dysfunction. 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drug effects</subject><subject>Enzymes</subject><subject>Fractionation</subject><subject>Free radicals</subject><subject>Heart</subject><subject>Hypoxia</subject><subject>Inhibitors</subject><subject>Ischemia</subject><subject>Kinases</subject><subject>Macrophages</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - enzymology</subject><subject>Mitochondria - metabolism</subject><subject>Mutation</subject><subject>Myocardial ischemia</subject><subject>Myocardial Ischemia - enzymology</subject><subject>Myocardial Ischemia - metabolism</subject><subject>Myocardial Ischemia - pathology</subject><subject>Oncology</subject><subject>Oxidase</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Oxygen</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Physiology</subject><subject>Proteases</subject><subject>Protein kinase A</subject><subject>Protein kinases</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - metabolism</subject><subject>Protein Transport - drug effects</subject><subject>Proteins</subject><subject>Proteolysis - drug effects</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - enzymology</subject><subject>Reperfusion Injury - metabolism</subject><subject>Reperfusion Injury - pathology</subject><subject>Rodents</subject><subject>Veterinary colleges</subject><subject>Veterinary medicine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9uK2zAQhk1p6W63fYPSGgqlvUiqkw-6KYSlh8BCoKdbMZbHiVLHSiV52bx95Y13icteFF1ISN_8Gv2aSZKXlMwpL-iHre1dB-18bzucE1IUlMlHyTmVnM1yRvjjk_VZ8sz7LSEZL_P8aXLGBOWkFOI8gdWNqSGYa0x9cOh9arq611inOxOs3tiudgbadO9sQNOlv00HHtNFusPaQECf6sPAObvDVKd2UIvn9cE3faeDsd3z5EkDrccX43yR_Pz86cfl19nV6svycnE107lkYdZAXsmCsZwBzXkhWNnUudS00iJmXWGlJYMyKzmTOQiJwCLRUIKElFXJOb9IXh919631anTHKyoEZSWlJI_E8kjUFrZq78wO3EFZMOp2w7q1AheMblEhk7JARoEgF00GUiJi1qAsNNQU6qj1cbytr6IVGrvgoJ2ITk86s1Fre614ITNChnTfjQLO_unRB7UzXmPbQoe2v82bS8lzSSP65h_04deN1BriA0zX2HivHkTVQhTRoUwQFqn5A1QcNe6MjqXUmLg_CXg_CYhMwJuwht57tfz-7f_Z1a8p-_aE3SC0YeNt2w8l46egOILaWe8dNvcmU6KGTrhzQw2doMZOiGGvTj_oPuiu9Plf6hwEZg</recordid><startdate>20131010</startdate><enddate>20131010</enddate><creator>Srinivasan, Satish</creator><creator>Spear, Joseph</creator><creator>Chandran, Karunakaran</creator><creator>Joseph, Joy</creator><creator>Kalyanaraman, Balaraman</creator><creator>Avadhani, Narayan G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131010</creationdate><title>Oxidative stress induced mitochondrial protein kinase A mediates cytochrome c oxidase dysfunction</title><author>Srinivasan, Satish ; Spear, Joseph ; Chandran, Karunakaran ; Joseph, Joy ; Kalyanaraman, Balaraman ; Avadhani, Narayan G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-fa6b972262a1637428fd69c1bc4538bebc92a8583296a49ea228ff10e008b8333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Activation</topic><topic>Adenylate cyclase</topic><topic>Animals</topic><topic>Antioxidants</topic><topic>Antioxidants - 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However, the mechanism of activation of the kinase under hypoxia remains unclear. It is also unclear if hypoxic stress activated PKA is different from the cAMP dependent mitochondrial PKA activity reported under normal physiological conditions. In this study using RAW 264.7 macrophages and in vitro perfused mouse heart system we investigated the nature of PKA activated under hypoxia. Limited protease treatment and digitonin fractionation of intact mitochondria suggests that higher mitochondrial PKA activity under hypoxia is mainly due to increased sequestration of PKA Catalytic α (PKAα) subunit in the mitochondrial matrix compartment. The increase in PKA activity is independent of mitochondrial cAMP and is not inhibited by adenylate cyclase inhibitor, KH7. Instead, activation of hypoxia-induced PKA is dependent on reactive oxygen species (ROS). H89, an inhibitor of PKA activity and the antioxidant Mito-CP prevented loss of CcO activity in macrophages under hypoxia and in mouse heart under ischemia/reperfusion injury. Substitution of wild type subunit Vb of CcO with phosphorylation resistant S40A mutant subunit attenuated the loss of CcO activity and reduced ROS production. These results provide a compelling evidence for hypoxia induced phosphorylation as a signal for CcO dysfunction. The results also describe a novel mechanism of mitochondrial PKA activation which is independent of mitochondrial cAMP, but responsive to ROS.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24130844</pmid><doi>10.1371/journal.pone.0077129</doi><tpages>e77129</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1441281106 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Adenylate cyclase Animals Antioxidants Antioxidants - pharmacology Biology Biophysics Cardiology Catalysis Cell Hypoxia - drug effects Cell Line Cell Respiration - drug effects Cyclic adenosine monophosphate Cyclic AMP Cyclic AMP-Dependent Protein Kinases - metabolism Cytochrome Cytochrome c Cytochrome oxidase Cytochrome-c oxidase Electron Transport Complex IV - genetics Electron Transport Complex IV - metabolism Endoplasmic reticulum Enzyme Activation - drug effects Enzymes Fractionation Free radicals Heart Hypoxia Inhibitors Ischemia Kinases Macrophages Mice Mitochondria Mitochondria - drug effects Mitochondria - enzymology Mitochondria - metabolism Mutation Myocardial ischemia Myocardial Ischemia - enzymology Myocardial Ischemia - metabolism Myocardial Ischemia - pathology Oncology Oxidase Oxidative stress Oxidative Stress - drug effects Oxygen Phosphorylation Phosphorylation - drug effects Physiology Proteases Protein kinase A Protein kinases Protein Subunits - genetics Protein Subunits - metabolism Protein Transport - drug effects Proteins Proteolysis - drug effects Reactive oxygen species Reactive Oxygen Species - metabolism Reperfusion Reperfusion Injury - enzymology Reperfusion Injury - metabolism Reperfusion Injury - pathology Rodents Veterinary colleges Veterinary medicine |
| title | Oxidative stress induced mitochondrial protein kinase A mediates cytochrome c oxidase dysfunction |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T07%3A13%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oxidative%20stress%20induced%20mitochondrial%20protein%20kinase%20A%20mediates%20cytochrome%20c%20oxidase%20dysfunction&rft.jtitle=PloS%20one&rft.au=Srinivasan,%20Satish&rft.date=2013-10-10&rft.volume=8&rft.issue=10&rft.spage=e77129&rft.epage=e77129&rft.pages=e77129-e77129&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0077129&rft_dat=%3Cgale_plos_%3EA478335402%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1441281106&rft_id=info:pmid/24130844&rft_galeid=A478335402&rft_doaj_id=oai_doaj_org_article_e2997e21a0e34f5a99eee5fe97cad1ad&rfr_iscdi=true |