title: Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model.
abstract: 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.
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States.
authors.forename: Lanying
authors.initials: L
authors.lastname: Song
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States.
authors.forename: Alfred
authors.initials: A
authors.lastname: Yu
authors.affiliation: Center for Neuroscience, University of California, Davis, Davis, CA 95616, United States; Department of Psychiatry & Behavioral Sciences, University of California, Davis, Davis, CA 95616, United States.
authors.forename: Karl
authors.initials: K
authors.lastname: Murray
authors.affiliation: Vet Med: Molecular Biosciences, University of California, Davis, Davis, CA 95616, United States. Electronic address: gcortopassi@ucdavis.edu.
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D025042:Amacrine Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001284:Atrophy; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D029242:Optic Atrophy, Hereditary, Leber / Q000378:metabolism / Q000473:pathology; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000502:physiology; D057907:Post-Synaptic Density / Q000378:metabolism / Q000473:pathology; D051245:Retinal Bipolar Cells / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: C534449:Ndufs4 protein, mouse; D042967:Electron Transport Complex I
keywords: Apoptosis; Mitochondrial complex I; Oxidase stress; Retinal bipolar cell; Retinal ganglion cell