Vielhaber 2013 Acta Neuropathol

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Vielhaber S, Debska-Vielhaber G, Peeva V, Schoeler S, Kudin AP, Minin I, Schreiber S, Dengler R, Kollewe K, Zuschratter W, Kornblum C, Zsurka G, Kunz WS (2013) Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion. Acta Neuropathol 125:245-56.

» PMID: 22926664

Vielhaber S, Debska-Vielhaber G, Peeva V, Schoeler S, Kudin AP, Minin I, Schreiber S, Dengler R, Kollewe K, Zuschratter W, Kornblum C, Zsurka G, Kunz WS (2013) Acta Neuropathol

Abstract: Charcot-Marie-Tooth neuropathy type 2A (CMT2A) is associated with heterozygous mutations in the mitochondrial protein mitofusin 2 (Mfn2) that is intimately involved with the outer mitochondrial membrane fusion machinery. The precise consequences of these mutations on oxidative phosphorylation are still a matter of dispute. Here, we investigate the functional effects of MFN2 mutations in skeletal muscle and cultured fibroblasts of four CMT2A patients applying high-resolution respirometry. While maximal activities of respiration of saponin-permeabilized muscle fibers and digitonin-permeabilized fibroblasts were only slightly affected by the MFN2 mutations, the sensitivity of active state oxygen consumption to azide, a cytochrome c oxidase (CIV) inhibitor, was increased. The observed dysfunction of the mitochondrial respiratory chain can be explained by a twofold decrease in mitochondrial DNA (mtDNA) copy numbers. The only patient without detectable alterations of respiratory chain in skeletal muscle also had a normal mtDNA copy number. We detected higher levels of mtDNA deletions in CMT2A patients, which were more pronounced in the patient without mtDNA depletion. Detailed analysis of mtDNA deletion breakpoints showed that many deleted molecules were lacking essential parts of mtDNA required for replication. This is in line with the lack of clonal expansion for the majority of observed mtDNA deletions. In contrast to the copy number reduction, deletions are unlikely to contribute to the detected respiratory impairment because of their minor overall amounts in the patients. Taken together, our findings corroborate the hypothesis that MFN2 mutations alter mitochondrial oxidative phosphorylation by affecting mtDNA replication.

Keywords: Charcot-Marie-Tooth neuropathy type 2A (CMT2A), Heterozygous mutations, Mitofusin 2 (Mfn2), Outer mitochondrial membrane fusion machinery, CMT2A patients, Azide, Mitochondrial DNA (mtDNA) copy numbers

O2k-Network Lab: DE Magdeburg Gellerich FN


Labels: MiParea: Respiration, mt-Biogenesis;mt-density, mtDNA;mt-genetics, mt-Medicine, Patients  Pathology: Cancer, Inherited 

Organism: Human  Tissue;cell: Skeletal muscle  Preparation: Permeabilized cells, Permeabilized tissue 

Regulation: Inhibitor, Threshold;excess capacity  Coupling state: OXPHOS  Pathway: CIV  HRR: Oxygraph-2k