title: Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology.
abstract: Mutations of the PINK1 gene are a cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase of unknown function which is widely expressed in both neuronal and non-neuronal cells. We have studied fibroblast cultures from four family members harbouring the homozygous p.Q456X mutation in PINK1, three of their wild-type relatives, one individual with the homozygous p.V170G mutation and five independent controls. Results showed bioenergetic abnormalities involving decreased activities of complexes I and IV along with increased activities of complexes II and III in the missense p.V170G mutant. There were increased basal levels of mitochondrial superoxide dismutase in these cells and an exaggerated increase of reduced glutathione in response to paraquat-induced free radical formation. Furthermore, swollen and enlarged mitochondria were observed in this sample. In the p.Q456X nonsense mutants, the respiratory chain enzymes were unaffected, but ATP levels were significantly decreased. These results confirm that mutations of PINK1 cause abnormal mitochondrial morphology, bioenergetic function and oxidative metabolism in human tissues but suggest that the biochemical consequences may vary between mutations.
authors.affiliation: Department of Neurology, Lübeck University, Lübeck, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Grünewald
authors.forename: M E
authors.initials: ME
authors.lastname: Gegg
authors.forename: J-W
authors.initials: JW
authors.lastname: Taanman
authors.forename: R H
authors.initials: RH
authors.lastname: King
authors.forename: N
authors.initials: N
authors.lastname: Kock
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.forename: A H V
authors.initials: AH
authors.lastname: Schapira
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D004579:Electron Transport / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011494:Protein Kinases / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000255:Adenosine Triphosphate; D018389:Codon, Nonsense; D005819:Genetic Markers; D011494:Protein Kinases; D013482:Superoxide Dismutase; D000099202:PTEN-Induced Putative Kinase