Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis
Identifieur interne : 001811 ( Ncbi/Merge ); précédent : 001810; suivant : 001812Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis
Auteurs : Shaida A. Andrabi ; George K. E. Umanah ; Calvin Chang ; Daniel A. Stevens ; Senthilkumar S. Karuppagounder ; Jean-Philippe Gagné [Canada] ; Guy G. Poirier [Canada] ; Valina L. Dawson ; Ted M. DawsonSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2014.
Abstract
Excessive activation of poly(ADP-ribose) (PAR) polymerase (PARP) is intimately linked to cell death in a variety of organ systems. It has long been thought that the cell death caused by excessive activation of PARP occurs through the catalytic consumption of NAD+ followed by reduction of ATP and bioenergetic collapse. This study shows that the bioenergetic collapse is caused not by the consumption of NAD+ but by PAR-dependent inhibition of hexokinase activity leading to defects in glycolysis. These results are consistent with the notion that cell death induced by excessive PARP activity (parthanatos) is an active cell-death program that is initiated by PAR signaling.
Url:
DOI: 10.1073/pnas.1405158111
PubMed: 24987120
PubMed Central: 4104885
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<author><name sortKey="Stevens, Daniel A" sort="Stevens, Daniel A" uniqKey="Stevens D" first="Daniel A." last="Stevens">Daniel A. Stevens</name>
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<affiliation><nlm:aff wicri:cut="; and" id="aff7">Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
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<author><name sortKey="Karuppagounder, Senthilkumar S" sort="Karuppagounder, Senthilkumar S" uniqKey="Karuppagounder S" first="Senthilkumar S." last="Karuppagounder">Senthilkumar S. Karuppagounder</name>
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<author><name sortKey="Dawson, Valina L" sort="Dawson, Valina L" uniqKey="Dawson V" first="Valina L." last="Dawson">Valina L. Dawson</name>
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<affiliation><nlm:aff wicri:cut="; and" id="aff7">Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
, Baltimore,<addr-line>MD</addr-line>
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<affiliation><nlm:aff wicri:cut=", and" id="aff4">Physiology</nlm:aff>
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<author><name sortKey="Dawson, Ted M" sort="Dawson, Ted M" uniqKey="Dawson T" first="Ted M." last="Dawson">Ted M. Dawson</name>
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<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="aff2"></nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
, Baltimore,<addr-line>MD</addr-line>
21205</nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff5">Pharmacology and Molecular Sciences</nlm:aff>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis</title>
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<affiliation><nlm:aff id="aff2"></nlm:aff>
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<author><name sortKey="Umanah, George K E" sort="Umanah, George K E" uniqKey="Umanah G" first="George K. E." last="Umanah">George K. E. Umanah</name>
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<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="aff2"></nlm:aff>
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<author><name sortKey="Chang, Calvin" sort="Chang, Calvin" uniqKey="Chang C" first="Calvin" last="Chang">Calvin Chang</name>
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<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
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</affiliation>
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<author><name sortKey="Stevens, Daniel A" sort="Stevens, Daniel A" uniqKey="Stevens D" first="Daniel A." last="Stevens">Daniel A. Stevens</name>
<affiliation><nlm:aff id="aff1">Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,</nlm:aff>
<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
, Baltimore,<addr-line>MD</addr-line>
21205</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Karuppagounder, Senthilkumar S" sort="Karuppagounder, Senthilkumar S" uniqKey="Karuppagounder S" first="Senthilkumar S." last="Karuppagounder">Senthilkumar S. Karuppagounder</name>
<affiliation><nlm:aff id="aff1">Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,</nlm:aff>
<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="aff2"></nlm:aff>
</affiliation>
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<author><name sortKey="Gagne, Jean Philippe" sort="Gagne, Jean Philippe" uniqKey="Gagne J" first="Jean-Philippe" last="Gagné">Jean-Philippe Gagné</name>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Centre de Recherche du CHU de Québec, Université Laval, Québec</institution>
,<country>Canada</country>
G1V 4G2</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Poirier, Guy G" sort="Poirier, Guy G" uniqKey="Poirier G" first="Guy G." last="Poirier">Guy G. Poirier</name>
<affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Centre de Recherche du CHU de Québec, Université Laval, Québec</institution>
,<country>Canada</country>
G1V 4G2</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author><name sortKey="Dawson, Valina L" sort="Dawson, Valina L" uniqKey="Dawson V" first="Valina L." last="Dawson">Valina L. Dawson</name>
<affiliation><nlm:aff id="aff1">Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,</nlm:aff>
<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="aff2"></nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
, Baltimore,<addr-line>MD</addr-line>
21205</nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff4">Physiology</nlm:aff>
</affiliation>
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<author><name sortKey="Dawson, Ted M" sort="Dawson, Ted M" uniqKey="Dawson T" first="Ted M." last="Dawson">Ted M. Dawson</name>
<affiliation><nlm:aff id="aff1">Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,</nlm:aff>
<wicri:noCountry code="subfield">Institute for Cell Engineering</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="aff2"></nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut="; and" id="aff7">Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
, Baltimore,<addr-line>MD</addr-line>
21205</nlm:aff>
</affiliation>
<affiliation><nlm:aff wicri:cut=", and" id="aff5">Pharmacology and Molecular Sciences</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title>
<idno type="ISSN">0027-8424</idno>
<idno type="eISSN">1091-6490</idno>
<imprint><date when="2014">2014</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><title>Significance</title>
<p>Excessive activation of poly(ADP-ribose) (PAR) polymerase (PARP) is intimately linked to cell death in a variety of organ systems. It has long been thought that the cell death caused by excessive activation of PARP occurs through the catalytic consumption of NAD<sup>+</sup>
followed by reduction of ATP and bioenergetic collapse. This study shows that the bioenergetic collapse is caused not by the consumption of NAD<sup>+</sup>
but by PAR-dependent inhibition of hexokinase activity leading to defects in glycolysis. These results are consistent with the notion that cell death induced by excessive PARP activity (parthanatos) is an active cell-death program that is initiated by PAR signaling.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id>
<journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id>
<journal-id journal-id-type="hwp">pnas</journal-id>
<journal-id journal-id-type="pmc">pnas</journal-id>
<journal-id journal-id-type="publisher-id">PNAS</journal-id>
<journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title>
</journal-title-group>
<issn pub-type="ppub">0027-8424</issn>
<issn pub-type="epub">1091-6490</issn>
<publisher><publisher-name>National Academy of Sciences</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">24987120</article-id>
<article-id pub-id-type="pmc">4104885</article-id>
<article-id pub-id-type="publisher-id">201405158</article-id>
<article-id pub-id-type="doi">10.1073/pnas.1405158111</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject>
<subj-group><subject>Cell Biology</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis</article-title>
<alt-title alt-title-type="short">Poly(ADP-ribose) inhibition of glycolysis</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Andrabi</surname>
<given-names>Shaida A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Umanah</surname>
<given-names>George K. E.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chang</surname>
<given-names>Calvin</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>c</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stevens</surname>
<given-names>Daniel A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Karuppagounder</surname>
<given-names>Senthilkumar S.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gagné</surname>
<given-names>Jean-Philippe</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Poirier</surname>
<given-names>Guy G.</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>e</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dawson</surname>
<given-names>Valina L.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>f</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dawson</surname>
<given-names>Ted M.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>a</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>b</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>d</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>g</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>1</sup>
</xref>
</contrib>
<aff id="aff1"><sup>a</sup>
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering,</aff>
<aff id="aff2">Departments of<sup>b</sup>
Neurology,</aff>
<aff id="aff3"><sup>c</sup>
Biomedical Engineering,</aff>
<aff id="aff4"><sup>f</sup>
Physiology, and</aff>
<aff id="aff5"><sup>g</sup>
Pharmacology and Molecular Sciences, and</aff>
<aff id="aff7"><sup>d</sup>
Solomon H. Snyder Department of Neuroscience,<institution>The Johns Hopkins University School of Medicine</institution>
, Baltimore,<addr-line>MD</addr-line>
21205; and</aff>
<aff id="aff6"><sup>e</sup>
<institution>Centre de Recherche du CHU de Québec, Université Laval, Québec</institution>
,<country>Canada</country>
G1V 4G2</aff>
</contrib-group>
<author-notes><corresp id="cor1"><sup>1</sup>
To whom correspondence may be addressed. Email: <email>sandrabi@jhmi.edu</email>
, <email>vdawson@jhmi.edu</email>
, or <email>tdawson@jhmi.edu</email>
.</corresp>
<fn fn-type="edited-by"><p>Edited by Salvador Moncada, University of Manchester, Manchester, United Kingdom, and approved June 12, 2014 (received for review March 19, 2014)</p>
</fn>
<fn fn-type="con"><p>Author contributions: S.A.A., V.L.D., and T.M.D. formulated the hypothesis and initiated and organized the study; S.A.A., G.K.E.U., V.L.D., and T.M.D. designed research; S.A.A., G.K.E.U., C.C., D.A.S., and S.S.K. performed research; J.-P.G. and G.G.P. contributed new reagents/analytic tools; S.A.A., G.K.E.U., C.C., D.A.S., S.S.K., J.-P.G., G.G.P., V.L.D., and T.M.D. analyzed data; and S.A.A., V.L.D., and T.M.D. wrote the paper.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>7</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>1</day>
<month>7</month>
<year>2014</year>
</pub-date>
<volume>111</volume>
<issue>28</issue>
<fpage>10209</fpage>
<lpage>10214</lpage>
<self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201405158.pdf"></self-uri>
<abstract abstract-type="executive-summary"><title>Significance</title>
<p>Excessive activation of poly(ADP-ribose) (PAR) polymerase (PARP) is intimately linked to cell death in a variety of organ systems. It has long been thought that the cell death caused by excessive activation of PARP occurs through the catalytic consumption of NAD<sup>+</sup>
followed by reduction of ATP and bioenergetic collapse. This study shows that the bioenergetic collapse is caused not by the consumption of NAD<sup>+</sup>
but by PAR-dependent inhibition of hexokinase activity leading to defects in glycolysis. These results are consistent with the notion that cell death induced by excessive PARP activity (parthanatos) is an active cell-death program that is initiated by PAR signaling.</p>
</abstract>
<abstract><p>Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated “parthanatos” in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD<sup>+</sup>
and energetic collapse, which have been thought to be caused by the consumption of cellular NAD<sup>+</sup>
by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD<sup>+</sup>
depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD<sup>+</sup>
depletion in <italic>N</italic>
-methyl-<italic>N</italic>
-nitroso-<italic>N</italic>
-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1–mediated mitochondrial dysfunction. Depleting neurons of NAD<sup>+</sup>
with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.</p>
</abstract>
<counts><page-count count="6"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Canada</li>
</country>
</list>
<tree><noCountry><name sortKey="Andrabi, Shaida A" sort="Andrabi, Shaida A" uniqKey="Andrabi S" first="Shaida A." last="Andrabi">Shaida A. Andrabi</name>
<name sortKey="Chang, Calvin" sort="Chang, Calvin" uniqKey="Chang C" first="Calvin" last="Chang">Calvin Chang</name>
<name sortKey="Dawson, Ted M" sort="Dawson, Ted M" uniqKey="Dawson T" first="Ted M." last="Dawson">Ted M. Dawson</name>
<name sortKey="Dawson, Valina L" sort="Dawson, Valina L" uniqKey="Dawson V" first="Valina L." last="Dawson">Valina L. Dawson</name>
<name sortKey="Karuppagounder, Senthilkumar S" sort="Karuppagounder, Senthilkumar S" uniqKey="Karuppagounder S" first="Senthilkumar S." last="Karuppagounder">Senthilkumar S. Karuppagounder</name>
<name sortKey="Stevens, Daniel A" sort="Stevens, Daniel A" uniqKey="Stevens D" first="Daniel A." last="Stevens">Daniel A. Stevens</name>
<name sortKey="Umanah, George K E" sort="Umanah, George K E" uniqKey="Umanah G" first="George K. E." last="Umanah">George K. E. Umanah</name>
</noCountry>
<country name="Canada"><noRegion><name sortKey="Gagne, Jean Philippe" sort="Gagne, Jean Philippe" uniqKey="Gagne J" first="Jean-Philippe" last="Gagné">Jean-Philippe Gagné</name>
</noRegion>
<name sortKey="Poirier, Guy G" sort="Poirier, Guy G" uniqKey="Poirier G" first="Guy G." last="Poirier">Guy G. Poirier</name>
</country>
</tree>
</affiliations>
</record>
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