Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair
Identifieur interne : 000865 ( Main/Exploration ); précédent : 000864; suivant : 000866Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair
Auteurs : Oliver Rothfuss ; Heike Fischer ; Takafumi Hasegawa ; Martina Maisel ; Petra Leitner ; Franziska Miesel ; Manu Sharma ; Antje Bornemann ; Daniela Berg ; Thomas Gasser ; Nadja Patenge [Allemagne]Source :
- Human Molecular Genetics [ 0964-6906 ] ; 2009-10-15.
Abstract
Mutations in the parkin gene are the most common cause of recessive familial Parkinson disease (PD). Parkin has been initially characterized as an ubiquitin E3 ligase, but the pathological relevance of this activity remains uncertain. Recently, an impressive amount of evidence has accumulated that parkin is involved in the maintenance of mitochondrial function and biogenesis. We used a human neuroblastoma cell line as a model to study the influence of endogenous parkin on mitochondrial genomic integrity. Using an unbiased chromatin immunoprecipitation approach, we found that parkin is associated physically with mitochondrial DNA (mtDNA) in proliferating as well as in differentiated SH-SY5Y cells. In vivo, the association of parkin with mtDNA could be confirmed in brain tissue of mouse and human origin. Replication and transcription of mtDNA were enhanced in SH-SY5Y cells over-expressing the parkin gene. The ability of parkin to support mtDNA-metabolism was impaired by pathogenic parkin point mutations. Most importantly, we show that parkin protects mtDNA from oxidative damage and stimulates mtDNA repair. Moreover, higher susceptibility of mtDNA to reactive oxygen species and reduced mtDNA repair capacity was observed in parkin-deleted fibroblasts of a PD patient. Our data indicate a novel role for parkin in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress.
Url:
DOI: 10.1093/hmg/ddp327
Affiliations:
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Takafumi" uniqKey="Hasegawa T" first="Takafumi" last="Hasegawa">Takafumi Hasegawa</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Maisel, Martina" sort="Maisel, Martina" uniqKey="Maisel M" first="Martina" last="Maisel">Martina Maisel</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Leitner, Petra" sort="Leitner, Petra" uniqKey="Leitner P" first="Petra" last="Leitner">Petra Leitner</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Miesel, Franziska" sort="Miesel, Franziska" uniqKey="Miesel F" first="Franziska" last="Miesel">Franziska Miesel</name><affiliation><wicri:noCountry code="syntax">???</wicri:noCountry></affiliation></author><author><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name><affiliation><wicri:noCountry 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wicri:rule="url">Allemagne</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-10-15">2009-10-15</date><biblScope unit="volume">18</biblScope><biblScope unit="issue">20</biblScope><biblScope unit="page" from="3832">3832</biblScope><biblScope unit="page" to="3850">3850</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">60F3A694D4808D9EB40AC90FBA48C3D657E588BB</idno><idno type="DOI">10.1093/hmg/ddp327</idno><idno type="ArticleID">ddp327</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Mutations in the parkin gene are the most common cause of recessive familial Parkinson disease (PD). Parkin has been initially characterized as an ubiquitin E3 ligase, but the pathological relevance of this activity remains uncertain. Recently, an impressive amount of evidence has accumulated that parkin is involved in the maintenance of mitochondrial function and biogenesis. We used a human neuroblastoma cell line as a model to study the influence of endogenous parkin on mitochondrial genomic integrity. Using an unbiased chromatin immunoprecipitation approach, we found that parkin is associated physically with mitochondrial DNA (mtDNA) in proliferating as well as in differentiated SH-SY5Y cells. In vivo, the association of parkin with mtDNA could be confirmed in brain tissue of mouse and human origin. Replication and transcription of mtDNA were enhanced in SH-SY5Y cells over-expressing the parkin gene. The ability of parkin to support mtDNA-metabolism was impaired by pathogenic parkin point mutations. Most importantly, we show that parkin protects mtDNA from oxidative damage and stimulates mtDNA repair. Moreover, higher susceptibility of mtDNA to reactive oxygen species and reduced mtDNA repair capacity was observed in parkin-deleted fibroblasts of a PD patient. Our data indicate a novel role for parkin in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country></list><tree><noCountry><name sortKey="Berg, Daniela" sort="Berg, Daniela" uniqKey="Berg D" first="Daniela" last="Berg">Daniela Berg</name><name sortKey="Bornemann, Antje" sort="Bornemann, Antje" uniqKey="Bornemann A" first="Antje" last="Bornemann">Antje Bornemann</name><name sortKey="Fischer, Heike" sort="Fischer, Heike" uniqKey="Fischer H" first="Heike" last="Fischer">Heike Fischer</name><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><name sortKey="Hasegawa, Takafumi" sort="Hasegawa, Takafumi" uniqKey="Hasegawa T" first="Takafumi" last="Hasegawa">Takafumi Hasegawa</name><name sortKey="Leitner, Petra" sort="Leitner, Petra" uniqKey="Leitner P" first="Petra" last="Leitner">Petra Leitner</name><name sortKey="Maisel, Martina" sort="Maisel, Martina" uniqKey="Maisel M" first="Martina" last="Maisel">Martina Maisel</name><name sortKey="Miesel, Franziska" sort="Miesel, Franziska" uniqKey="Miesel F" first="Franziska" last="Miesel">Franziska Miesel</name><name sortKey="Rothfuss, Oliver" sort="Rothfuss, Oliver" uniqKey="Rothfuss O" first="Oliver" last="Rothfuss">Oliver Rothfuss</name><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name></noCountry><country name="Allemagne"><noRegion><name sortKey="Patenge, Nadja" sort="Patenge, Nadja" uniqKey="Patenge N" first="Nadja" last="Patenge">Nadja Patenge</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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