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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mitochondrial Contagion Induced by Parkin Deficiency in <italic>Drosophila</italic> Hearts and Its Containment by Suppressing Mitofusin</title><author><name sortKey="Bhandari, Poonam" sort="Bhandari, Poonam" uniqKey="Bhandari P" first="Poonam" last="Bhandari">Poonam Bhandari</name></author><author><name sortKey="Song, Moshi" sort="Song, Moshi" uniqKey="Song M" first="Moshi" last="Song">Moshi Song</name></author><author><name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name></author><author><name sortKey="Burelle, Yan" sort="Burelle, Yan" uniqKey="Burelle Y" first="Yan" last="Burelle">Yan Burelle</name></author><author><name sortKey="Dorn, Gerald W" sort="Dorn, Gerald W" uniqKey="Dorn G" first="Gerald W." last="Dorn">Gerald W. Dorn</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24192653</idno><idno type="pmc">4392818</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392818</idno><idno type="RBID">PMC:4392818</idno><idno type="doi">10.1161/CIRCRESAHA.114.302734</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000698</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000698</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mitochondrial Contagion Induced by Parkin Deficiency in <italic>Drosophila</italic> Hearts and Its Containment by Suppressing Mitofusin</title><author><name sortKey="Bhandari, Poonam" sort="Bhandari, Poonam" uniqKey="Bhandari P" first="Poonam" last="Bhandari">Poonam Bhandari</name></author><author><name sortKey="Song, Moshi" sort="Song, Moshi" uniqKey="Song M" first="Moshi" last="Song">Moshi Song</name></author><author><name sortKey="Chen, Yun" sort="Chen, Yun" uniqKey="Chen Y" first="Yun" last="Chen">Yun Chen</name></author><author><name sortKey="Burelle, Yan" sort="Burelle, Yan" uniqKey="Burelle Y" first="Yan" last="Burelle">Yan Burelle</name></author><author><name sortKey="Dorn, Gerald W" sort="Dorn, Gerald W" uniqKey="Dorn G" first="Gerald W." last="Dorn">Gerald W. Dorn</name></author></analytic><series><title level="j">Circulation research</title><idno type="ISSN">0009-7330</idno><idno type="eISSN">1524-4571</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>Rationale</title><p id="P1">Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood.</p></sec><sec id="S2"><title>Objective</title><p id="P2">We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in <italic>Drosophila</italic> heart tubes.</p></sec><sec id="S3"><title>Methods and Results</title><p id="P3">Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because <italic>Drosophila</italic> lack most of these redundant genes, we examined heart tubes of <italic>parkin</italic> knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.</p></sec></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>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0047103</journal-id><journal-id journal-id-type="pubmed-jr-id">2974</journal-id><journal-id journal-id-type="nlm-ta">Circ Res</journal-id><journal-id journal-id-type="iso-abbrev">Circ. Res.</journal-id><journal-title-group><journal-title>Circulation research</journal-title></journal-title-group><issn pub-type="ppub">0009-7330</issn><issn pub-type="epub">1524-4571</issn></journal-meta><article-meta><article-id pub-id-type="pmid">24192653</article-id><article-id pub-id-type="pmc">4392818</article-id><article-id pub-id-type="doi">10.1161/CIRCRESAHA.114.302734</article-id><article-id pub-id-type="manuscript">NIHMS677538</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mitochondrial Contagion Induced by Parkin Deficiency in <italic>Drosophila</italic> Hearts and Its Containment by Suppressing Mitofusin</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Bhandari</surname><given-names>Poonam</given-names></name></contrib><contrib contrib-type="author"><name><surname>Song</surname><given-names>Moshi</given-names></name></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Yun</given-names></name></contrib><contrib contrib-type="author"><name><surname>Burelle</surname><given-names>Yan</given-names></name></contrib><contrib contrib-type="author"><name><surname>Dorn</surname><given-names>Gerald W.</given-names><suffix>II</suffix></name></contrib><aff id="A1">Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO (P.B., M.S., Y.C., G.W.D.); and Department of Biomedical Sciences, University of Montreal, Quebec, Canada (Y.B.)</aff></contrib-group><author-notes><corresp id="cor1">Correspondence to Gerald W. Dorn, II, MD, Washington University Center for Pharmacogenomics, 660 S Euclid Ave, Campus Box 8220, St Louis, MO 63110. <email>gdorn@dom.wustl.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>7</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>05</day><month>11</month><year>2013</year></pub-date><pub-date pub-type="ppub"><day>17</day><month>1</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>10</day><month>4</month><year>2015</year></pub-date><volume>114</volume><issue>2</issue><fpage>257</fpage><lpage>265</lpage><pmc-comment>elocation-id from pubmed: 10.1161/CIRCRESAHA.114.302734</pmc-comment>
<permissions><copyright-statement>© 2013 American Heart Association, Inc.</copyright-statement><copyright-year>2013</copyright-year></permissions><abstract><sec id="S1"><title>Rationale</title><p id="P1">Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood.</p></sec><sec id="S2"><title>Objective</title><p id="P2">We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in <italic>Drosophila</italic> heart tubes.</p></sec><sec id="S3"><title>Methods and Results</title><p id="P3">Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because <italic>Drosophila</italic> lack most of these redundant genes, we examined heart tubes of <italic>parkin</italic> knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy.</p></sec><sec id="S4"><title>Conclusions</title><p id="P4">Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.</p></sec></abstract><kwd-group><kwd>cardiomyopathies</kwd><kwd>mitochondrial dynamics</kwd><kwd>mitochondrial degradation</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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