The mutant human ND4 subunit of complex I induces optic neuropathy in the mouse

Invest Ophthalmol Vis Sci. 2007 Jan;48(1):1-10. doi: 10.1167/iovs.06-0789.


Purpose: To produce a mouse model of Leber hereditary optic neuropathy.

Methods: A mutant ND4 subunit made compatible with the universal genetic code and containing an arginine-to-histidine substitution at residue 340, or a synthetic normal human ND4 gene was delivered to the mouse visual system. The expression and effects of the mutant ND4 gene on the optic nerve and cultured retinal ganglion cells was assessed by magnetic resonance imaging, immunohistochemistry, and light and transmission electron microscopy.

Results: The ATPc mitochondrial targeting sequence directed the allotopically expressed mutant human R340H and wild-type ND4FLAG polypeptides into mitochondria. Expression of normal human ND4 in murine mitochondria posed no ocular toxicity. In contrast, the mutant ND4 disrupted mitochondrial cytoarchitecture, elevated reactive oxygen species, induced swelling of the optic nerve head, and induced apoptosis, with a progressive demise of ganglion cells in the retina and their axons comprising the optic nerve.

Conclusions: Allotopic expression of the mutant human R340H ND4 subunit of complex I replicated the hallmarks of human mitochondrial disease in the mouse. In contrast, ocular expression of the wild-type human ND4 subunit in lower mammals appears safe, suggesting that it may be useful for treatment of patients with Leber hereditary optic neuropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Apoptosis
  • Cells, Cultured
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / ultrastructure
  • Dependovirus / genetics
  • Disease Models, Animal*
  • Electron Transport Complex I / genetics*
  • Fibroblasts / metabolism
  • Gene Expression Regulation / physiology*
  • Genetic Therapy*
  • Genetic Vectors
  • Immunohistochemistry
  • Isoenzymes / genetics
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Inbred DBA
  • Microscopy, Electron, Transmission
  • Optic Atrophy, Hereditary, Leber / genetics*
  • Optic Atrophy, Hereditary, Leber / pathology
  • Optic Nerve / metabolism
  • Optic Nerve / ultrastructure
  • Reactive Oxygen Species / metabolism
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / ultrastructure
  • Transfection


  • DNA, Mitochondrial
  • Isoenzymes
  • Reactive Oxygen Species
  • Adenosine Triphosphate
  • Electron Transport Complex I