Mitochondrial complex I deficiency leads to inflammation and retinal ganglion cell death in the Ndufs4 mouse

Hum Mol Genet. 2015 May 15;24(10):2848-60. doi: 10.1093/hmg/ddv045. Epub 2015 Feb 4.


Mitochondrial complex I (NADH dehydrogenase) is a major contributor to neuronal energetics, and mutations in complex I lead to vision loss. Functional, neuroanatomical and transcriptional consequences of complex I deficiency were investigated in retinas of the Ndufs4 knockout mouse. Whole-eye ERGs and multielectrode arrays confirmed a major retinal ganglion cell functional loss at P32, and retinal ganglion cell loss at P42. RNAseq demonstrated a mild and then sharp increase in innate immune and inflammatory retinal transcripts at P22 and P33, respectively, which were confirmed with QRT-PCR. Intraperitoneal injection of the inflammogen lipopolysaccharide further reduced retinal ganglion cell function in Ndufs4 KO, supporting the connection between inflammatory activation and functional loss. Complex I deficiency in the retina clearly caused innate immune and inflammatory markers to increase coincident with loss of vision, and RGC functional loss. How complex I incites inflammation and functional loss is not clear, but could be the result of misfolded complex I generating a 'non-self' response, and induction of innate immune response transcripts was observed before functional loss at P22, including β-2 microglobulin and Cx3cr1, and during vision loss at P31 (B2m, Tlr 2, 3, 4, C1qa, Cx3cr1 and Fas). These data support the hypothesis that mitochondrial complex I dysfunction in the retina triggers an innate immune and inflammatory response that results in loss of retinal ganglion cell function and death, as in Leber's hereditary Optic Neuropathy and suggests novel therapeutic routes to counter mitochondrial defects that contribute to vision loss.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Death
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / immunology
  • Female
  • Gene Knockout Techniques
  • Immunity, Innate / genetics
  • Inflammation / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / immunology
  • Mitochondrial Diseases / physiopathology*
  • Retina / immunology
  • Retina / physiopathology*
  • Retinal Ganglion Cells / physiology*


  • Ndufs4 protein, mouse
  • Electron Transport Complex I

Supplementary concepts

  • Mitochondrial complex I deficiency