Mitofusin 2 mutations affect mitochondrial function by mitochondrial DNA depletion

Acta Neuropathol. 2013 Feb;125(2):245-56. doi: 10.1007/s00401-012-1036-y. Epub 2012 Aug 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Mitochondrial Proteins
  • Succinate Dehydrogenase
  • Electron Transport Complex IV
  • Citrate (si)-Synthase
  • GTP Phosphohydrolases
  • MFN2 protein, human