title: Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium.
abstract: The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using13C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD+precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195; jianhai.du@wvumedicine.org jrchao@uw.edu.|Department of Ophthalmology, University of Washington, Seattle, WA 98109.|Department of Ophthalmology, West Virginia University, Morgantown, WV 26506.
authors.forename: Jianhai
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98109.
authors.forename: Aya
authors.initials: A
authors.lastname: Yanagida
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98109.
authors.forename: Kaitlen
authors.initials: K
authors.lastname: Knight
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98109.
authors.forename: Abbi L
authors.initials: AL
authors.lastname: Engel
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195.
authors.forename: Anh Huan
authors.initials: AH
authors.lastname: Vo
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195.
authors.forename: Connor
authors.initials: C
authors.lastname: Jankowski
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195.
authors.forename: Martin
authors.initials: M
authors.lastname: Sadilek
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195.
authors.forename: Van Thi Bao
authors.initials: VT
authors.lastname: Tran
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98109.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Manson
authors.affiliation: Center for Blood Cancers and Oncology, St. David's South Austin Medical Center, Austin, TX 78704.
authors.forename: Aravind
authors.initials: A
authors.lastname: Ramakrishnan
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195.|Department of Ophthalmology, University of Washington, Seattle, WA 98109.
authors.forename: James B
authors.initials: JB
authors.lastname: Hurley
authors.affiliation: Department of Ophthalmology, University of Washington, Seattle, WA 98109; jianhai.du@wvumedicine.org jrchao@uw.edu.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Chao
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D002244:Carbon / Q000737:chemistry*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005123:Eye / Q000196:embryology*; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D006367:HeLa Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry*; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009243:NAD / Q000737:chemistry; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000196:embryology* / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D007656:Ketoglutaric Acids; D009243:NAD; D002244:Carbon; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D011065:Poly(ADP-ribose) Polymerases; D010100:Oxygen
keywords: RPE; age-related macular degeneration; metabolism; oxidative stress; reductive carboxylation