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Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart
In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H 2 O 2 by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H 2 O 2 elimination via isocitrate dehydrogenase and nicotina...
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| Published in: | Basic research in cardiology 2020-09, Vol.115 (5), p.53, Article 53 |
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| container_issue | 5 |
| container_start_page | 53 |
| container_title | Basic research in cardiology |
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| creator | Wagner, Michael Bertero, Edoardo Nickel, Alexander Kohlhaas, Michael Gibson, Gary E. Heggermont, Ward Heymans, Stephane Maack, Christoph |
| description | In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H
2
O
2
by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H
2
O
2
elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in
skeletal
muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H
2
O
2
emission in
cardiac
mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H
2
O
2
emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H
2
O
2
-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H
2
O
2
emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H
2
O
2
-eliminating capacity increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H
2
O
2
emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H
2
O
2
elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure. |
| doi_str_mv | 10.1007/s00395-020-0815-1 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7399685</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2430379345</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-301970f3be351db9641597a8c857c2cf52fd08eabfaa0425a078487251b0be233</originalsourceid><addsrcrecordid>eNp1ks2KFDEUhQtRnHb0AdxIwI2b0puf6ko2wjD-jDDoQl2HVOpWd8aqpE1Sjf1Ygs_hM5mmxnEUXCVwvnvuPXCq6jGF5xSgfZEAuGpqYFCDpE1N71QrKnj5SOB3qxVwgFoKJk-qByldAVCxXtP71QlnrZBMqlX14yOOaLPbI3l_9uqC2DBNs3fWZBc8GWKYyM_v9RfMYTPO2USTkfS4PfQxbNCbhCQHMrkc7Db4PjozkhyNT7eJXcQ9-pxIRLOsCt8ORSNph9ZhIkOI07Jw9j3GwvWzdX5TrvG9OwqJOE_yFskWTcwPq3uDGRM-un5Pq89vXn86v6gvP7x9d352WVvRQq45UNXCwDvkDe07tRa0Ua2RVjatZXZo2NCDRNMNxoBgjYFWCtmyhnbQIeP8tHq5-O7mbsLelhDRjHoX3WTiQQfj9N-Kd1u9CXvdcqXWsikGz64NYvg6Y8p6csniOBqPYU6aCQ68VVwc0af_oFdhjr7EKxRTilElVKHoQtkYUoo43BxDQR87oZdO6NIJfeyEpmXmye0UNxO_S1AAtgCpSH6D8c_q_7v-ArN6yLM</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2429921949</pqid></control><display><type>article</type><title>Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart</title><source>Springer Nature</source><creator>Wagner, Michael ; Bertero, Edoardo ; Nickel, Alexander ; Kohlhaas, Michael ; Gibson, Gary E. ; Heggermont, Ward ; Heymans, Stephane ; Maack, Christoph</creator><creatorcontrib>Wagner, Michael ; Bertero, Edoardo ; Nickel, Alexander ; Kohlhaas, Michael ; Gibson, Gary E. ; Heggermont, Ward ; Heymans, Stephane ; Maack, Christoph</creatorcontrib><description>In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H
2
O
2
by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H
2
O
2
elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in
skeletal
muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H
2
O
2
emission in
cardiac
mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H
2
O
2
emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H
2
O
2
-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H
2
O
2
emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H
2
O
2
-eliminating capacity increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H
2
O
2
emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H
2
O
2
elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.</description><identifier>ISSN: 0300-8428</identifier><identifier>ISSN: 1435-1803</identifier><identifier>EISSN: 1435-1803</identifier><identifier>DOI: 10.1007/s00395-020-0815-1</identifier><identifier>PMID: 32748289</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adenosine triphosphate ; Animals ; Cardiology ; Cardiomyocytes ; Cell Respiration ; Chains ; Congestive heart failure ; Dehydrogenase ; Dehydrogenases ; Depletion ; Electron transport chain ; Emission analysis ; Emissions control ; Heart failure ; Hydrogen peroxide ; Isocitrate dehydrogenase ; Ketoglutarate Dehydrogenase Complex - metabolism ; Ketoglutaric acid ; Krebs cycle ; Malate ; Medicine ; Medicine & Public Health ; Mice, Inbred C57BL ; Mitochondria ; Mitochondria, Heart - metabolism ; Muscles ; Myocytes ; Myocytes, Cardiac - metabolism ; NAD - metabolism ; NADH ; NADP Transhydrogenases - metabolism ; NADPH ; Nicotinamide ; Nicotinamide adenine dinucleotide ; Nucleotides ; Original Contribution ; Oxidative stress ; Oxoglutarate dehydrogenase (lipoamide) ; Pyruvic acid ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Rotenone ; Single-Cell Analysis ; Skeletal muscle ; Substrate inhibition ; Substrates ; Superoxide ; Tricarboxylic acid cycle</subject><ispartof>Basic research in cardiology, 2020-09, Vol.115 (5), p.53, Article 53</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-301970f3be351db9641597a8c857c2cf52fd08eabfaa0425a078487251b0be233</citedby><cites>FETCH-LOGICAL-c470t-301970f3be351db9641597a8c857c2cf52fd08eabfaa0425a078487251b0be233</cites><orcidid>0000-0003-3694-4559</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32748289$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wagner, Michael</creatorcontrib><creatorcontrib>Bertero, Edoardo</creatorcontrib><creatorcontrib>Nickel, Alexander</creatorcontrib><creatorcontrib>Kohlhaas, Michael</creatorcontrib><creatorcontrib>Gibson, Gary E.</creatorcontrib><creatorcontrib>Heggermont, Ward</creatorcontrib><creatorcontrib>Heymans, Stephane</creatorcontrib><creatorcontrib>Maack, Christoph</creatorcontrib><title>Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart</title><title>Basic research in cardiology</title><addtitle>Basic Res Cardiol</addtitle><addtitle>Basic Res Cardiol</addtitle><description>In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H
2
O
2
by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H
2
O
2
elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in
skeletal
muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H
2
O
2
emission in
cardiac
mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H
2
O
2
emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H
2
O
2
-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H
2
O
2
emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H
2
O
2
-eliminating capacity increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H
2
O
2
emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H
2
O
2
elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.</description><subject>Adenosine triphosphate</subject><subject>Animals</subject><subject>Cardiology</subject><subject>Cardiomyocytes</subject><subject>Cell Respiration</subject><subject>Chains</subject><subject>Congestive heart failure</subject><subject>Dehydrogenase</subject><subject>Dehydrogenases</subject><subject>Depletion</subject><subject>Electron transport chain</subject><subject>Emission analysis</subject><subject>Emissions control</subject><subject>Heart failure</subject><subject>Hydrogen peroxide</subject><subject>Isocitrate dehydrogenase</subject><subject>Ketoglutarate Dehydrogenase Complex - metabolism</subject><subject>Ketoglutaric acid</subject><subject>Krebs cycle</subject><subject>Malate</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice, Inbred C57BL</subject><subject>Mitochondria</subject><subject>Mitochondria, Heart - metabolism</subject><subject>Muscles</subject><subject>Myocytes</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>NAD - metabolism</subject><subject>NADH</subject><subject>NADP Transhydrogenases - metabolism</subject><subject>NADPH</subject><subject>Nicotinamide</subject><subject>Nicotinamide adenine dinucleotide</subject><subject>Nucleotides</subject><subject>Original Contribution</subject><subject>Oxidative stress</subject><subject>Oxoglutarate dehydrogenase (lipoamide)</subject><subject>Pyruvic acid</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Rotenone</subject><subject>Single-Cell Analysis</subject><subject>Skeletal muscle</subject><subject>Substrate inhibition</subject><subject>Substrates</subject><subject>Superoxide</subject><subject>Tricarboxylic acid cycle</subject><issn>0300-8428</issn><issn>1435-1803</issn><issn>1435-1803</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp1ks2KFDEUhQtRnHb0AdxIwI2b0puf6ko2wjD-jDDoQl2HVOpWd8aqpE1Sjf1Ygs_hM5mmxnEUXCVwvnvuPXCq6jGF5xSgfZEAuGpqYFCDpE1N71QrKnj5SOB3qxVwgFoKJk-qByldAVCxXtP71QlnrZBMqlX14yOOaLPbI3l_9uqC2DBNs3fWZBc8GWKYyM_v9RfMYTPO2USTkfS4PfQxbNCbhCQHMrkc7Db4PjozkhyNT7eJXcQ9-pxIRLOsCt8ORSNph9ZhIkOI07Jw9j3GwvWzdX5TrvG9OwqJOE_yFskWTcwPq3uDGRM-un5Pq89vXn86v6gvP7x9d352WVvRQq45UNXCwDvkDe07tRa0Ua2RVjatZXZo2NCDRNMNxoBgjYFWCtmyhnbQIeP8tHq5-O7mbsLelhDRjHoX3WTiQQfj9N-Kd1u9CXvdcqXWsikGz64NYvg6Y8p6csniOBqPYU6aCQ68VVwc0af_oFdhjr7EKxRTilElVKHoQtkYUoo43BxDQR87oZdO6NIJfeyEpmXmye0UNxO_S1AAtgCpSH6D8c_q_7v-ArN6yLM</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Wagner, Michael</creator><creator>Bertero, Edoardo</creator><creator>Nickel, Alexander</creator><creator>Kohlhaas, Michael</creator><creator>Gibson, Gary E.</creator><creator>Heggermont, Ward</creator><creator>Heymans, Stephane</creator><creator>Maack, Christoph</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M7Z</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3694-4559</orcidid></search><sort><creationdate>20200901</creationdate><title>Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart</title><author>Wagner, Michael ; Bertero, Edoardo ; Nickel, Alexander ; Kohlhaas, Michael ; Gibson, Gary E. ; Heggermont, Ward ; Heymans, Stephane ; Maack, Christoph</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-301970f3be351db9641597a8c857c2cf52fd08eabfaa0425a078487251b0be233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenosine triphosphate</topic><topic>Animals</topic><topic>Cardiology</topic><topic>Cardiomyocytes</topic><topic>Cell Respiration</topic><topic>Chains</topic><topic>Congestive heart failure</topic><topic>Dehydrogenase</topic><topic>Dehydrogenases</topic><topic>Depletion</topic><topic>Electron transport chain</topic><topic>Emission analysis</topic><topic>Emissions control</topic><topic>Heart failure</topic><topic>Hydrogen peroxide</topic><topic>Isocitrate dehydrogenase</topic><topic>Ketoglutarate Dehydrogenase Complex - metabolism</topic><topic>Ketoglutaric acid</topic><topic>Krebs cycle</topic><topic>Malate</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice, Inbred C57BL</topic><topic>Mitochondria</topic><topic>Mitochondria, Heart - metabolism</topic><topic>Muscles</topic><topic>Myocytes</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>NAD - metabolism</topic><topic>NADH</topic><topic>NADP Transhydrogenases - metabolism</topic><topic>NADPH</topic><topic>Nicotinamide</topic><topic>Nicotinamide adenine dinucleotide</topic><topic>Nucleotides</topic><topic>Original Contribution</topic><topic>Oxidative stress</topic><topic>Oxoglutarate dehydrogenase (lipoamide)</topic><topic>Pyruvic acid</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Rotenone</topic><topic>Single-Cell Analysis</topic><topic>Skeletal muscle</topic><topic>Substrate inhibition</topic><topic>Substrates</topic><topic>Superoxide</topic><topic>Tricarboxylic acid cycle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wagner, Michael</creatorcontrib><creatorcontrib>Bertero, Edoardo</creatorcontrib><creatorcontrib>Nickel, Alexander</creatorcontrib><creatorcontrib>Kohlhaas, Michael</creatorcontrib><creatorcontrib>Gibson, Gary E.</creatorcontrib><creatorcontrib>Heggermont, Ward</creatorcontrib><creatorcontrib>Heymans, Stephane</creatorcontrib><creatorcontrib>Maack, Christoph</creatorcontrib><collection>Springer Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Basic research in cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wagner, Michael</au><au>Bertero, Edoardo</au><au>Nickel, Alexander</au><au>Kohlhaas, Michael</au><au>Gibson, Gary E.</au><au>Heggermont, Ward</au><au>Heymans, Stephane</au><au>Maack, Christoph</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart</atitle><jtitle>Basic research in cardiology</jtitle><stitle>Basic Res Cardiol</stitle><addtitle>Basic Res Cardiol</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>115</volume><issue>5</issue><spage>53</spage><pages>53-</pages><artnum>53</artnum><issn>0300-8428</issn><issn>1435-1803</issn><eissn>1435-1803</eissn><abstract>In heart failure, a functional block of complex I of the respiratory chain provokes superoxide generation, which is transformed to H
2
O
2
by dismutation. The Krebs cycle produces NADH, which delivers electrons to complex I, and NADPH for H
2
O
2
elimination via isocitrate dehydrogenase and nicotinamide nucleotide transhydrogenase (NNT). At high NADH levels, α-ketoglutarate dehydrogenase (α-KGDH) is a major source of superoxide in
skeletal
muscle mitochondria with low NNT activity. Here, we analyzed how α-KGDH and NNT control H
2
O
2
emission in
cardiac
mitochondria. In cardiac mitochondria from NNT-competent BL/6N mice, H
2
O
2
emission is equally low with pyruvate/malate (P/M) or α-ketoglutarate (α-KG) as substrates. Complex I inhibition with rotenone increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria, which is potentiated by depleting H
2
O
2
-eliminating capacity. Conversely, in NNT-deficient BL/6J mitochondria, H
2
O
2
emission is higher with α-KG than with P/M as substrate, and further potentiated by complex I blockade. Prior depletion of H
2
O
2
-eliminating capacity increases H
2
O
2
emission from P/M, but not α-KG respiring mitochondria. In cardiac myocytes, downregulation of α-KGDH activity impaired dynamic mitochondrial redox adaptation during workload transitions, without increasing H
2
O
2
emission. In conclusion, NADH from α-KGDH selectively shuttles to NNT for NADPH formation rather than to complex I of the respiratory chain for ATP production. Therefore, α-KGDH plays a key role for H
2
O
2
elimination, but is not a relevant source of superoxide in heart. In heart failure, α-KGDH/NNT-dependent NADPH formation ameliorates oxidative stress imposed by complex I blockade. Downregulation of α-KGDH may, therefore, predispose to oxidative stress in heart failure.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>32748289</pmid><doi>10.1007/s00395-020-0815-1</doi><orcidid>https://orcid.org/0000-0003-3694-4559</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0300-8428 |
| ispartof | Basic research in cardiology, 2020-09, Vol.115 (5), p.53, Article 53 |
| issn | 0300-8428 1435-1803 1435-1803 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7399685 |
| source | Springer Nature |
| subjects | Adenosine triphosphate Animals Cardiology Cardiomyocytes Cell Respiration Chains Congestive heart failure Dehydrogenase Dehydrogenases Depletion Electron transport chain Emission analysis Emissions control Heart failure Hydrogen peroxide Isocitrate dehydrogenase Ketoglutarate Dehydrogenase Complex - metabolism Ketoglutaric acid Krebs cycle Malate Medicine Medicine & Public Health Mice, Inbred C57BL Mitochondria Mitochondria, Heart - metabolism Muscles Myocytes Myocytes, Cardiac - metabolism NAD - metabolism NADH NADP Transhydrogenases - metabolism NADPH Nicotinamide Nicotinamide adenine dinucleotide Nucleotides Original Contribution Oxidative stress Oxoglutarate dehydrogenase (lipoamide) Pyruvic acid Reactive oxygen species Reactive Oxygen Species - metabolism Rotenone Single-Cell Analysis Skeletal muscle Substrate inhibition Substrates Superoxide Tricarboxylic acid cycle |
| title | Selective NADH communication from α-ketoglutarate dehydrogenase to mitochondrial transhydrogenase prevents reactive oxygen species formation under reducing conditions in the heart |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T22%3A10%3A29IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Selective%20NADH%20communication%20from%20%CE%B1-ketoglutarate%20dehydrogenase%20to%20mitochondrial%20transhydrogenase%20prevents%20reactive%20oxygen%20species%20formation%20under%20reducing%20conditions%20in%20the%20heart&rft.jtitle=Basic%20research%20in%20cardiology&rft.au=Wagner,%20Michael&rft.date=2020-09-01&rft.volume=115&rft.issue=5&rft.spage=53&rft.pages=53-&rft.artnum=53&rft.issn=0300-8428&rft.eissn=1435-1803&rft_id=info:doi/10.1007/s00395-020-0815-1&rft_dat=%3Cproquest_pubme%3E2430379345%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c470t-301970f3be351db9641597a8c857c2cf52fd08eabfaa0425a078487251b0be233%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2429921949&rft_id=info:pmid/32748289&rfr_iscdi=true |