The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes

Biochim Biophys Acta. 2008 Oct;1783(10):1707-17. doi: 10.1016/j.bbamcr.2008.04.018. Epub 2008 May 6.


Leber's Hereditary Optic Neuropathy (LHON) was the first maternally inherited mitochondrial disease identified and is now considered the most prevalent mitochondrial disorder. LHON patients harbor mutations in mitochondrial DNA (mtDNA). In about 90% of cases, the genes involved encode proteins of the respiratory chain complex I. Even though the molecular bases are known since 20 years almost all remains to be done regarding physiopathology and therapy. In this study, we report a severe decrease of complex I activity in cultured skin fibroblasts isolated from two LHON patients harboring mutations in ND4 or ND1 genes. Most importantly, we were able to restore sustainably (a) the ability to grow on galactose, (b) the ATP synthesis rate and (c) the complex I activity, initially impaired in these cells. Our strategy consisted of forcing mRNAs from nuclearly-encoded ND1 and ND4 genes to localize to the mitochondrial surface. The rescue of the respiratory chain defect observed was possible by discreet amounts of hybrid mRNAs and fusion proteins demonstrating the efficiency of their mitochondrial import. Hence, we confirmed here for two mitochondrial genes located in the organelle that the optimized allotopic expression approach represents a powerful tool that could ultimately be applied in human therapy for LHON.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Adolescent
  • Adult
  • Cells, Cultured
  • Culture Media
  • Electron Transport
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Galactose
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Male
  • Mutation / genetics
  • NADH Dehydrogenase / genetics*
  • NADH Dehydrogenase / metabolism*
  • Protein Binding
  • RNA, Messenger / genetics
  • Transgenes / genetics


  • Culture Media
  • NADH dehydrogenase subunit 4
  • RNA, Messenger
  • Adenosine Triphosphate
  • NADH Dehydrogenase
  • NADH dehydrogenase subunit 1, human
  • Galactose