title: ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.
abstract: Mutations in ATP13A2 cause autosomal-recessive parkinsonism (Kufor-Rakeb syndrome; KRS). Because several other parkinsonism-associated proteins have been connected to mitochondrial function and mitophagy, we studied the impact of endogenous mutations in ATPase type 13A2 (ATP13A2) on mitochondria in fibroblasts from KRS patients compared with controls. In patients, we detected decreased adenosine triphosphate (ATP) synthesis rates, increased mitochondrial DNA levels, a higher frequency of mitochondrial DNA lesions, increased oxygen consumption rates, and increased fragmentation of the mitochondrial network. Importantly, overexpression of wild-type ATP13A2 rescued the respiration phenotype. These findings collectively suggest that ATP13A2 contributes to the maintenance of a healthy mitochondrial pool, supporting the hypothesis that impaired mitochondrial clearance represents an important pathogenic mechanism underlying KRS.
authors.affiliation: Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Grünewald
authors.forename: Björn
authors.initials: B
authors.lastname: Arns
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Rakovic
authors.forename: Alexander
authors.initials: A
authors.lastname: Münchau
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C514983:ATP13A2 protein, human; D006180:Proton-Translocating ATPases