Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system

Biochem Biophys Res Commun. 2010 Oct 8;401(1):26-31. doi: 10.1016/j.bbrc.2010.08.143. Epub 2010 Sep 15.


The phenotypes of mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) have been proposed to be strictly regulated by the proportion of wild-type and pathogenically mutated mtDNAs. More specifically, it is thought that the onset of the disease phenotype occurs when cells cannot maintain the proper mitochondrial function because of an over-abundance of pathological mtDNA. Therapies that cause a decrease in the pathogenic mtDNA population have been proposed as a treatment for mitochondrial diseases, but these therapies are difficult to apply in practice. In this report, we present a novel concept: to improve mitochondrial disease phenotypes via an increase in the absolute copy number of the wild-type mtDNA population in pathogenic cells even when the relative proportion of mtDNA genotypes remains unchanged. We have succeeded in ameliorating the typical symptoms of mitochondrial disease in a model mouse line by the over-expression of the mitochondrial transcription factor A (Tfam) followed by an increase of the mtDNA copy number. This new concept should lead to the development of a novel therapeutic treatment for mitochondrial diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Mitochondrial / genetics*
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Electron Transport Complex IV / genetics
  • Electron Transport Complex IV / metabolism
  • Gene Dosage
  • Gene Expression
  • Genetic Therapy / methods*
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / pathology
  • Mitochondrial Diseases / therapy*
  • Mitochondrial Proteins / genetics*
  • Transcription Factors / genetics*


  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • Transcription Factors
  • mitochondrial transcription factor A
  • Electron Transport Complex IV