Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration
Toshihide Kurihara,
Peter D Westenskow,
Marin L Gantner,
Yoshihiko Usui,
Andrew Schultz,
Stephen Bravo,
Edith Aguilar,
Carli Wittgrove,
Mollie SH Friedlander,
Liliana P Paris,
Emily Chew,
Gary Siuzdak,
Martin Friedlander
Affiliations
Toshihide Kurihara
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Peter D Westenskow
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States; The Lowy Medical Research Institute, La Jolla, United States
Marin L Gantner
The Lowy Medical Research Institute, La Jolla, United States
Yoshihiko Usui
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Andrew Schultz
Center for Metabolomics, The Scripps Research Institute, La Jolla, United States
Stephen Bravo
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Edith Aguilar
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Carli Wittgrove
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Mollie SH Friedlander
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Liliana P Paris
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, United States
Emily Chew
National Eye Institute, National Institutes of Health, Bethesda, United States
Gary Siuzdak
Center for Metabolomics, The Scripps Research Institute, La Jolla, United States
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.
