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

Lanying Song, Alfred Yu, Karl D Murray, Gino A Cortopassi

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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, 20–24 days. 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.

Original languageEnglish (US)
Pages (from-to)232-244
Number of pages13
JournalBrain Research
StatePublished - Feb 15 2017


  • Apoptosis
  • Mitochondrial complex I
  • Oxidase stress
  • Retinal bipolar cell
  • Retinal ganglion cell

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Developmental Biology
  • Clinical Neurology


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