ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome.

Anne Grünewald, Björn Arns, Philip Seibler, Aleksandar Rakovic, Alexander Münchau, Alfredo Ramirez, Carolyn M Sue, Christine Klein

Section of Clinical and Molecular Neurogenetics, Department of Neurology, University of Lübeck, Lübeck, Germany.

Neurobiology of aging 2012 Aug

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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. Copyright © 2012 Elsevier Inc. All rights reserved.

Citation

Anne Grünewald, Björn Arns, Philip Seibler, Aleksandar Rakovic, Alexander Münchau, Alfredo Ramirez, Carolyn M Sue, Christine Klein. ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome. Neurobiology of aging. 2012 Aug;33(8):1843.e1-7