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@ARTICLE{Vielhaber:136764,
      author       = {Vielhaber, Stefan and Debska-Vielhaber, Grazyna and Peeva,
                      Viktoriya and Schoeler, Susanne and Kudin, Alexei P and
                      Minin, Irina and Schreiber, Stefanie and Dengler, Reinhard
                      and Kollewe, Katja and Zuschratter, Werner and Kornblum,
                      Cornelia and Zsurka, Gábor and Kunz, Wolfram S},
      title        = {{M}itofusin 2 mutations affect mitochondrial function by
                      mitochondrial {DNA} depletion.},
      journal      = {Acta neuropathologica},
      volume       = {125},
      number       = {2},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2020-03086},
      pages        = {245-256},
      year         = {2013},
      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 (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.},
      keywords     = {Adult / Blotting, Western / Cell Separation / Cells,
                      Cultured / Charcot-Marie-Tooth Disease: genetics / Citrate
                      (si)-Synthase: metabolism / DNA Repair / DNA, Mitochondrial:
                      physiology / Electron Transport: genetics / Electron
                      Transport: physiology / Electron Transport Complex IV:
                      metabolism / Female / Fibroblasts: physiology / GTP
                      Phosphohydrolases: genetics / Gene Dosage / Humans / Male /
                      Microscopy, Electron / Mitochondria: genetics /
                      Mitochondria: physiology / Mitochondrial Proteins: genetics
                      / Muscle Fibers, Skeletal: physiology / Muscle, Skeletal:
                      physiology / Mutation: genetics / Oxygen Consumption:
                      physiology / Succinate Dehydrogenase: metabolism / Young
                      Adult / DNA, Mitochondrial (NLM Chemicals) / Mitochondrial
                      Proteins (NLM Chemicals) / Succinate Dehydrogenase (NLM
                      Chemicals) / Electron Transport Complex IV (NLM Chemicals) /
                      Citrate (si)-Synthase (NLM Chemicals) / GTP
                      Phosphohydrolases (NLM Chemicals) / MFN2 protein, human (NLM
                      Chemicals)},
      cin          = {AG Düzel / Magdeburg common / U Clinical Researchers -
                      Magdeburg},
      ddc          = {610},
      cid          = {I:(DE-2719)5000006 / I:(DE-2719)6000015 /
                      I:(DE-2719)7000000},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22926664},
      doi          = {10.1007/s00401-012-1036-y},
      url          = {https://pub.dzne.de/record/136764},
}