Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion
| Autor: | Irina Minin, Reinhard Dengler, Viktoriya Peeva, Grazyna Debska-Vielhaber, Gábor Zsurka, Wolfram S. Kunz, Katja Kollewe, Cornelia Kornblum, Susanne Schoeler, Werner Zuschratter, Alexei P. Kudin, Stefan Vielhaber, Stefanie Schreiber |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
DNA Repair Muscle Fibers Skeletal MFN2 Respiratory chain Gene Dosage Cell Separation GTP Phosphohydrolases MFN2 protein human Charcot-Marie-Tooth Disease Cells Cultured physiology [Muscle Skeletal] physiology [Fibroblasts] Mitochondria physiology [Electron Transport] metabolism [Citrate (si)-Synthase] Succinate Dehydrogenase Mitochondrial respiratory chain physiology [Muscle Fibers Skeletal] Female genetics [Mitochondrial Proteins] genetics [Charcot-Marie-Tooth Disease] Adult Mitochondrial DNA genetics [GTP Phosphohydrolases] DNA repair Blotting Western genetics [Mutation] Oxidative phosphorylation Citrate (si)-Synthase Biology DNA Mitochondrial Pathology and Forensic Medicine Electron Transport metabolism [Succinate Dehydrogenase] Mitochondrial Proteins Electron Transport Complex IV Cellular and Molecular Neuroscience Mitofusin-2 Young Adult Oxygen Consumption Cytochrome c oxidase Humans physiology [Mitochondria] ddc:610 Muscle Skeletal metabolism [Electron Transport Complex IV] physiology [Oxygen Consumption] Fibroblasts genetics [Electron Transport] Molecular biology physiology [DNA Mitochondrial] Microscopy Electron Mutation biology.protein Neurology (clinical) genetics [Mitochondria] |
| Zdroj: | Acta neuropathologica 125(2), 245-256 (2012). doi:10.1007/s00401-012-1036-y |
| DOI: | 10.1007/s00401-012-1036-y |
| Popis: | 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 (COX) 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. |
| Databáze: | OpenAIRE |
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