title: Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair.
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.
authors.affiliation: Department for Neurodegenerative Diseases, Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rothfuss
authors.forename: Heike
authors.initials: H
authors.lastname: Fischer
authors.forename: Takafumi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Martina
authors.initials: M
authors.lastname: Maisel
authors.forename: Petra
authors.initials: P
authors.lastname: Leitner
authors.forename: Franziska
authors.initials: F
authors.lastname: Miesel
authors.forename: Manu
authors.initials: M
authors.lastname: Sharma
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Nadja
authors.initials: N
authors.lastname: Patenge
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D054629:Genome, Mitochondrial; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein