Parkin protects Mitochondrial Genome Integrity and supports Mitochondrial DNA Repair.

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Hum Mol Genet 2009 Jul;

Authors: Oliver Rothfuss, Heike Fischer, Takafumi Hasegawa, Martina Maisel, Petra Leitner, Franziska Miesel, Manu Sharma, Antje Bornemann, Daniela Berg, Thomas Gasser, Nadja Patenge

Center of Neurology and Hertie Institute for Clinical Brain Research, Department for Neurodegenerative Diseases, University of Tübingen, 72076 Tübingen, Germany.

Mutations in the parkin gene are the most common cause of recessive familial Parkinson disease. 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 in proliferating as well as in differentiated SH-SY5Y cells. In vivo, the association of parkin with mitochondrial DNA could be confirmed in brain tissue of mouse and human origin. Replication and transcription of mitochondrial DNA were enhanced in SH-SY5Y cells over-expressing the parkin gene. The ability of parkin to support mitochondrial DNA-metabolism was impaired by pathogenic parkin point mutations. Most importantly, we show that parkin protects mitochondrial DNA from oxidative damage and stimulates mitochondrial DNA repair. Moreover, higher susceptibility of mitochondrial DNA to ROS and reduced mitochondrial DNA 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.

PMID: 19617636 [PubMed - as supplied by publisher]

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