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

doi:10.1016/j.neurobiolaging.2011.12.035

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^*

^*Corresponding author for this work

115 Citations (Scopus)

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.

Original language	English
Journal	Neurobiology of Aging
Volume	33
Issue number	8
ISSN	0197-4580
DOIs	https://doi.org/10.1016/j.neurobiolaging.2011.12.035
Publication status	Published - 01.08.2012

Funding

Dr. Grünewald received research support from the German Research Foundation, and Dr. Klein received research support from the Volkswagen Foundation and the Hermann and Lilly Schilling Foundation, and Dr. Sue received research support from the Australian Brain Foundation. Appendix A

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 10 Reduced Inequalities

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10.1016/j.neurobiolaging.2011.12.035

Cite this

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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.",

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AU - Grünewald, Anne

AU - Arns, Björn

AU - Seibler, Philip

AU - Rakovic, Aleksandar

AU - Münchau, Alexander

AU - Ramirez, Alfredo

AU - Sue, Carolyn M.

AU - Klein, Christine

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N2 - 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.

AB - 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.

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

Abstract

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UN SDGs

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