title: PGC-1α signaling coordinates susceptibility to metabolic and oxidative injury in the inner retina.
abstract: Retinal ganglion cells (RGCs), used as a common model of central nervous system injury, are particularly vulnerable to metabolic and oxidative damage. However, molecular mechanisms underlying this sensitivity have not been determined in vivo. PGC-1α (encoded by PPARGC1A) regulates adaptive metabolism and oxidative stress responses in a tissue- and cell-specific manner. Aberrant PGC-1α signaling is implicated in neurodegeneration, but the mechanism underlying its role in central nervous system injury remains unclear. We provide evidence from a mouse model that PGC-1α expression and activity are induced in adult retina in response to metabolic and oxidative challenge. Deletion of Ppargc1a dramatically increased RGC loss, in association with dysregulated expression of PGC-1α target metabolic and oxidative stress response genes, including Hmox1 (encoding HO-1), Tfam, and Vegfa. Vehicle-treated and naive Ppargc1a(-/-) mice also showed mild RGC loss, and surprisingly prominent and consistent retinal astrocyte reactivity. These cells critically regulate metabolic homeostasis in the inner retina. We show that PGC-1α signaling (not previously studied in glia) regulates detoxifying astrocyte responses to hypoxic and oxidative stresses. Finally, PGC-1α expression was modulated in the inner retina with age and in a model of chronic optic neuropathy. These data implicate PGC-1α signaling as an important regulator of astrocyte reactivity and RGC homeostasis to coordinate pathogenic susceptibility to metabolic and oxidative injury in the inner retina.
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors: Xiaoxin
authors: X
authors: Guo
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors: Ebernella S
authors: ES
authors: Dason
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Genetic and Molecular Epidemiology Unit, Department of Preventive Medicine and Public Health, University of Valencia School of Medicine, Valencia, Spain; Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBER), University of Valencia, Valencia, Spain.
authors: Vicente
authors: V
authors: Zanon-Moreno
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Genetic and Molecular Epidemiology Unit, Department of Preventive Medicine and Public Health, University of Valencia School of Medicine, Valencia, Spain; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors: Qi
authors: Q
authors: Jiang
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors: Adrian
authors: A
authors: Nahirnyj
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
authors: Darren
authors: D
authors: Chan
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada; Department of Optometry, University of Waterloo, Waterloo, Ontario, Canada.
authors: John G
authors: JG
authors: Flanagan
authors: Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Genetic and Molecular Epidemiology Unit, Department of Preventive Medicine and Public Health, University of Valencia School of Medicine, Valencia, Spain; Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: jsivak@uhnres.utoronto.ca.
authors: Jeremy M
authors: JM
authors: Sivak
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors