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      Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium

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          In the vertebrate eye, a monolayer of cells, called the retinal pigment epithelium (RPE), is between the choroidal blood supply and the retina. The RPE provides metabolic support for the retina, including delivery of glucose and other nutrients. Here, we show that reductive carboxylation of α-ketoglutarate, a type of metabolism that supports growth and survival of cancer cells, is a prominent feature of RPE cells. We show that extreme oxidative stress can overwhelm the reductive carboxylation pathway. However, we also found that the RPE can be protected from extreme oxidative stress by supplementation with an NAD + precursor or α-ketoglutarate.


          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. Using 13C 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.

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          Author and article information

          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          20 December 2016
          1 December 2016
          : 113
          : 51
          : 14710-14715
          aDepartment of Biochemistry, University of Washington , Seattle, WA 98195;
          bDepartment of Ophthalmology, University of Washington , Seattle, WA 98109;
          cDepartment of Ophthalmology, West Virginia University , Morgantown, WV 26506;
          dDepartment of Chemistry, University of Washington , Seattle, WA 98195;
          eCenter for Blood Cancers and Oncology, St. David’s South Austin Medical Center , Austin, TX 78704
          Author notes
          1To whom correspondence may be addressed. Email: jianhai.du@ 123456wvumedicine.org or jrchao@ 123456uw.edu .

          Edited by Martin Friedlander, The Scripps Research Institute, La Jolla, CA, and accepted by Editorial Board Member Jeremy Nathans October 24, 2016 (received for review March 20, 2016)

          Author contributions: J.D., J.B.H., and J.R.C. designed research; J.D., A.Y., K.K., A.L.E., A.H.V., C.J., V.T.B.T., and M.A.M. performed research; M.S. and A.R. contributed new reagents/analytic tools; J.D., A.Y., K.K., A.L.E., C.J., M.S., M.A.M., J.B.H., and J.R.C. analyzed data; and J.D., K.K., J.B.H., and J.R.C. wrote the paper.

          PMC5187684 PMC5187684 5187684 201604572
          Page count
          Pages: 6
          Funded by: HHS | NIH | National Eye Institute (NEI) 100000053
          Award ID: EY06641
          Funded by: HHS | NIH | National Eye Institute (NEI) 100000053
          Award ID: EY017863
          Funded by: HHS | NIH | National Eye Institute (NEI) 100000053
          Award ID: EY026030
          Funded by: HHS | NIH | National Eye Institute (NEI) 100000053
          Award ID: EY019714
          Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
          Award ID: DK082783
          Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) 100000050
          Award ID: HL099993
          Funded by: HHS | NIH | National Eye Institute (NEI) 100000053
          Award ID: EY001730
          Funded by: Bill and Melinda Gates Foundation 100000865
          Award ID: OPP1048681
          Funded by: Research to Prevent Blindness (RPB) 100001818
          Award ID: Unrestricted Grant
          Biological Sciences


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