title: Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration.
abstract: Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kurihara
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.|The Lowy Medical Research Institute, La Jolla, United States.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Westenskow
authors.affiliation: The Lowy Medical Research Institute, La Jolla, United States.
authors.forename: Marin L
authors.initials: ML
authors.lastname: Gantner
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Usui
authors.affiliation: Center for Metabolomics, The Scripps Research Institute, La Jolla, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Schultz
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Bravo
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Edith
authors.initials: E
authors.lastname: Aguilar
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Carli
authors.initials: C
authors.lastname: Wittgrove
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Mollie Sh
authors.initials: MSh
authors.lastname: Friedlander
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Liliana P
authors.initials: LP
authors.lastname: Paris
authors.affiliation: National Eye Institute, National Institutes of Health, Bethesda, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Chew
authors.affiliation: Center for Metabolomics, The Scripps Research Institute, La Jolla, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States.
authors.forename: Martin
authors.identifier: 0000-0003-4238-9651
authors.initials: M
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D000860:Hypoxia; D008268:Macular Degeneration / Q000503:physiopathology*; D051379:Mice; D010786:Photoreceptor Cells / Q000502:physiology*; D055213:Retinal Pigment Epithelium / Q000502:physiology*; D013312:Stress, Physiological
keywords: age-related macular degeneration; cell biology; hypoxia; mouse; neuroscience; neurovascular crosstalk