Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model

Brain Res. 2017 Feb 15;1657:232-244. doi: 10.1016/j.brainres.2016.12.019. Epub 2016 Dec 24.


Inherited mitochondrial complex 1 deficiency causes Leber's hereditary Optic Neuropathy (LHON) and retinal ganglion cell (RGC) degeneration, and optic neuropathies are common in many inherited mitochondrial diseases. How mitochondrial defects pathomechanistically trigger optic neuropathy remains unclear. We observe that complex 1-deficient Ndufs4-/- mice present with acute vision loss around p30, and this vision loss is coincident with an 'inflammatory wave'. In order to understand what causes the inflammatory wave we explored retinal pathology that occurs from p20-p30. The results indicated that in the period p20-p30 in Ndufs4-/- retinas, there is: significant reduction in bipolar cells, RGC dendritic atrophy, reduced PSD95, increased oxidative stress as manifested by increased 4HNE, HO1 and Cuzn-SOD, increased mitochondrial biogenesis and increased apoptosis. These precede the major induction of 'inflammatory wave' at p30 shown previously, but occur earlier than frank RGC loss at p42. In general, complex 1 deficiency in retina triggers oxidative stress and mitochondrial respiratory dysfunction that causes death of the most sensitive cells, including bipolar cells and their synaptic contacts and amacrine cells in the early period, 20-24days. The early death of these cells is the likely precursor to the sharp rise in inflammatory molecules that occurs at day 30 and coincides with vision loss, and greatly precedes the death of RGCs that occurs at p42. These data suggest that metabolic antioxidant support of the most sensitive cells in the retina, or anti-inflammatory suppression of the consequences of their death, are both rational strategies for mitochondrial blinding disease.

Keywords: Apoptosis; Mitochondrial complex I; Oxidase stress; Retinal bipolar cell; Retinal ganglion cell.

MeSH terms

  • Amacrine Cells / metabolism
  • Amacrine Cells / pathology
  • Animals
  • Apoptosis / physiology
  • Atrophy
  • Dendrites / metabolism
  • Dendrites / pathology
  • Disease Models, Animal
  • Disease Progression
  • Electron Transport Complex I / deficiency*
  • Electron Transport Complex I / genetics
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Optic Atrophy, Hereditary, Leber / metabolism
  • Optic Atrophy, Hereditary, Leber / pathology
  • Organelle Biogenesis
  • Oxidative Stress / physiology
  • Post-Synaptic Density / metabolism
  • Post-Synaptic Density / pathology
  • Retinal Bipolar Cells / metabolism*
  • Retinal Bipolar Cells / pathology
  • Retinal Ganglion Cells / metabolism*
  • Retinal Ganglion Cells / pathology


  • Ndufs4 protein, mouse
  • Electron Transport Complex I