Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Retinoid Metabolism in the Degeneration of Pten-Deficient Mouse Retinal Pigment Epithelium

  • Kim, You-Joung (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Park, Sooyeon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Ha, Taejeong (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Kim, Seungbeom (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Lim, Soyeon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • You, Han (School of Life Sciences, Xiamen University) ;
  • Kim, Jin Woo (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2021.05.31
  • Accepted : 2021.06.07
  • Published : 2021.08.31
Download PDF
⟨ Previous Next ⟩

Abstract

In vertebrate eyes, the retinal pigment epithelium (RPE) provides structural and functional homeostasis to the retina. The RPE takes up retinol (ROL) to be dehydrogenated and isomerized to 11-cis-retinaldehyde (11-cis-RAL), which is a functional photopigment in mammalian photoreceptors. As excessive ROL is toxic, the RPE must also establish mechanisms to protect against ROL toxicity. Here, we found that the levels of retinol dehydrogenases (RDHs) are commonly decreased in phosphatase tensin homolog (Pten)-deficient mouse RPE, which degenerates due to elevated ROL and that can be rescued by feeding a ROL-free diet. We also identified that RDH gene expression is regulated by forkhead box O (FOXO) transcription factors, which are inactivated by hyperactive Akt in the Pten-deficient mouse RPE. Together, our findings suggest that a homeostatic pathway comprising PTEN, FOXO, and RDH can protect the RPE from ROL toxicity.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grants funded by Korean Ministry of Science and ICT (MSIT) (2017R1A2B3002862 and 2018R1A5A1024261; J.W.K.); the grant funded by Samsung Foundation of Science and Technology (SSTF-BA1802-10; J.W.K.).

References

  1. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994). The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330, 1029-1035. https://doi.org/10.1056/NEJM199404143301501
  2. Bainbridge, J.W., Smith, A.J., Barker, S.S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G.E., Stockman, A., Tyler, N., et al. (2008). Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358, 2231-2239. https://doi.org/10.1056/NEJMoa0802268
  3. Brown, E.E., DeWeerd, A.J., Ildefonso, C.J., Lewin, A.S., and Ash, J.D. (2019). Mitochondrial oxidative stress in the retinal pigment epithelium (RPE) led to metabolic dysfunction in both the RPE and retinal photoreceptors. Redox Biol. 24, 101201. https://doi.org/10.1016/j.redox.2019.101201
  4. Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J., and Greenberg, M.E. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868. https://doi.org/10.1016/S0092-8674(00)80595-4
  5. Brunet, A., Datta, S.R., and Greenberg, M.E. (2001). Transcriptiondependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297-305. https://doi.org/10.1016/S0959-4388(00)00211-7
  6. Cunningham, T.J. and Duester, G. (2015). Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat. Rev. Mol. Cell Biol. 16, 110-123. https://doi.org/10.1038/nrm3932
  7. de Oliveira, M.R., da Rocha, R.F., Pasquali, M.A.d.B., and Moreira, J.C.F. (2012). The effects of vitamin A supplementation for 3 months on adult rat nigrostriatal axis: Increased monoamine oxidase enzyme activity, mitochondrial redox dysfunction, increased β-amyloid1-40 peptide and TNF-α contents, and susceptibility of mitochondria to an in vitro H2O2 challenge. Brain Res. Bull. 87, 432-444. https://doi.org/10.1016/j.brainresbull.2012.01.005
  8. DiPalma, J.R. and Ritchie, D.M. (1977). Vitamin toxicity. Ann. Rev. Pharmacol. Toxicol. 17, 133-148. https://doi.org/10.1146/annurev.pa.17.040177.001025
  9. Ferreira, R., Napoli, J., Enver, T., Bernardino, L., and Ferreira, L. (2020). Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine. Nat. Commun. 11, 4265. https://doi.org/10.1038/s41467-020-18042-2
  10. Finnemann, S.C. and Chang, Y. (2008). Photoreceptor-RPE interactions. In Visual Transduction and Non-Visual Light Perception, J. Tombran-Tink and C.J. Barnstable, eds. (Totowa, NJ: Humana Press), pp. 67-86.
  11. Garita-Hernandez, M., Lampic, M., Chaffiol, A., Guibbal, L., Routet, F., Santos-Ferreira, T., Gasparini, S., Borsch, O., Gagliardi, G., Reichman, S., et al. (2019). Restoration of visual function by transplantation of optogenetically engineered photoreceptors. Nat. Commun. 10, 4524. https://doi.org/10.1038/s41467-019-12330-2
  12. Hess, A.F. and Myers, V.C. (1919). Carotinemia: a new clinical picture. JAMA 73, 1743-1745. https://doi.org/10.1001/jama.1919.02610490007003
  13. Imanishi, Y., Batten, M.L., Piston, D.W., Baehr, W., and Palczewski, K. (2004). Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. J. Cell Biol. 164, 373-383. https://doi.org/10.1083/jcb.200311079
  14. Jin, M., Li, S., Moghrabi, W.N., Sun, H., and Travis, G.H. (2005). Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 122, 449-459. https://doi.org/10.1016/j.cell.2005.06.042
  15. Kang, K.H., Lemke, G., and Kim, J.W. (2009). The PI3K-PTEN tug-of-war, oxidative stress and retinal degeneration. Trends Mol. Med. 15, 191-198.
  16. Kelley, M.W., Turner, J.K., and Reh, T.A. (1994). Retinoic acid promotes differentiation of photoreceptors in vitro. Development 120, 2091-2102. https://doi.org/10.1242/dev.120.8.2091
  17. Kim, J.W., Kang, K.H., Burrola, P., Mak, T.W., and Lemke, G. (2008). Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium. Genes Dev. 22, 3147-3157. https://doi.org/10.1101/gad.1700108
  18. Kim, Y.K., Wassef, L., Chung, S., Jiang, H., Wyss, A., Blaner, W.S., and Quadro, L. (2011). β-Carotene and its cleavage enzyme β-carotene-15,15'-oxygenase (CMOI) affect retinoid metabolism in developing tissues. FASEB J. 25, 1641-1652. https://doi.org/10.1096/fj.10-175448
  19. Krinsky, N.I. and Johnson, E.J. (2005). Carotenoid actions and their relation to health and disease. Mol. Aspects Med. 26, 459-516. https://doi.org/10.1016/j.mam.2005.10.001
  20. Le, D., Lim, S., Min, K.W., Park, J.W., Kim, Y., Ha, T., Moon, K.H., Wagner, K.U., and Kim, J.W. (2021). Tsg101 is necessary for the establishment and maintenance of mouse retinal pigment epithelial cell polarity. Mol. Cells 44, 168-178. https://doi.org/10.14348/molcells.2021.0027
  21. Lee, E.J., Kim, N., Kang, K.H., and Kim, J.W. (2011). Phosphorylation/inactivation of PTEN by Akt-independent PI3K signaling in retinal pigment epithelium. Biochem. Biophys. Res. Commun. 414, 384-389. https://doi.org/10.1016/j.bbrc.2011.09.083
  22. Leid, M., Kastner, P., and Chambon, P. (1992). Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem. Sci. 17, 427-433. https://doi.org/10.1016/0968-0004(92)90014-Z
  23. Liden, M. and Eriksson, U. (2006). Understanding retinol metabolism: structure and function of retinol dehydrogenases. J. Biol. Chem. 281, 13001-13004. https://doi.org/10.1074/jbc.R500027200
  24. Maden, M. (2002). Retinoid signalling in the development of the central nervous system. Nat. Rev. Neurosci. 3, 843-853. https://doi.org/10.1038/nrn963
  25. Michalik, L. and Wahli, W. (2007). Guiding ligands to nuclear receptors. Cell 129, 649-651. https://doi.org/10.1016/j.cell.2007.05.001
  26. Moon, K.H., Kim, H.T., Lee, D., Rao, M.B., Levine, E.M., Lim, D.S., and Kim, J.W. (2018). Differential expression of NF2 in neuroepithelial compartments is necessary for mammalian eye development. Dev. Cell 44, 13-28.e3. https://doi.org/10.1016/j.devcel.2017.11.011
  27. Morimura, H., Fishman, G.A., Grover, S.A., Fulton, A.B., Berson, E.L., and Dryja, T.P. (1998). Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc. Natl. Acad. Sci. U. S. A. 95, 3088-3093. https://doi.org/10.1073/pnas.95.6.3088
  28. Nagao, A. (2009). Absorption and function of dietary carotenoids. Forum Nutr. 61, 55-63.
  29. Niederreither, K. and Dolle, P. (2008). Retinoic acid in development: towards an integrated view. Nat. Rev. Genet. 9, 541-553. https://doi.org/10.1038/nrg2340
  30. Obsil, T. and Obsilova, V. (2011). Structural basis for DNA recognition by FOXO proteins. Biochim. Biophys. Acta 1813, 1946-1953. https://doi.org/10.1016/j.bbamcr.2010.11.025
  31. Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Valanis, B., Williams, J.H., et al. (1996). Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150-1155. https://doi.org/10.1056/NEJM199605023341802
  32. Pares, X., Farres, J., Kedishvili, N., and Duester, G. (2008). Medium- and short-chain dehydrogenase/reductase gene and protein families: medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism. Cell. Mol. Life Sci. 65, 3936-3949. https://doi.org/10.1007/s00018-008-8591-3
  33. Parish, C.A., Hashimoto, M., Nakanishi, K., Dillon, J., and Sparrow, J. (1998). Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc. Natl. Acad. Sci. U. S. A. 95, 14609-14613. https://doi.org/10.1073/pnas.95.25.14609
  34. Putting, B.J., Zweypfenning, R.C., Vrensen, G.F., Oosterhuis, J.A., and van Best, J.A. (1992). Blood-retinal barrier dysfunction at the pigment epithelium induced by blue light. Invest. Ophthalmol. Vis. Sci. 33, 3385-3393.
  35. Radu, R.A., Mata, N.L., Bagla, A., and Travis, G.H. (2004). Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 101, 5928-5933. https://doi.org/10.1073/pnas.0308302101
  36. Redmond, T.M., Yu, S., Lee, E., Bok, D., Hamasaki, D., Chen, N., Goletz, P., Ma, J.X., Crouch, R.K., and Pfeifer, K. (1998). Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nat. Genet. 20, 344-351. https://doi.org/10.1038/3813
  37. Richter, C., Gogvadze, V., Laffranchi, R., Schlapbach, R., Schweizer, M., Suter, M., Walter, P., and Yaffee, M. (1995). Oxidants in mitochondria: from physiology to diseases. Biochim. Biophys. Acta 1271, 67-74. https://doi.org/10.1016/0925-4439(95)00012-S
  38. Ruiz, A., Ghyselinck, N.B., Mata, N., Nusinowitz, S., Lloyd, M., Dennefeld, C., Chambon, P., and Bok, D. (2007). Somatic ablation of the Lrat gene in the mouse retinal pigment epithelium drastically reduces its retinoid storage. Invest. Ophthalmol. Vis. Sci. 48, 5377-5387. https://doi.org/10.1167/iovs.07-0673
  39. Saari, J.C. and Bredberg, D.L. (1989). Lecithin:retinol acyltransferase in retinal pigment epithelial microsomes. J. Biol. Chem. 264, 8636-8640. https://doi.org/10.1016/S0021-9258(18)81839-7
  40. Saari, J.C., Bredberg, D.L., and Farrell, D.F. (1993). Retinol esterification in bovine retinal pigment epithelium: reversibility of lecithin:retinol acyltransferase. Biochem. J. 291 (Pt 3), 697-700. https://doi.org/10.1042/bj2910697
  41. Sahu, B. and Maeda, A. (2016). Retinol dehydrogenases regulate vitamin A metabolism for visual function. Nutrients 8, 746. https://doi.org/10.3390/nu8110746
  42. Sommer, A. (2008). Vitamin a deficiency and clinical disease: an historical overview. J. Nutr. 138, 1835-1839. https://doi.org/10.1093/jn/138.10.1835
  43. Stambolic, V., Suzuki, A., de la Pompa, J.L., Brothers, G.M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J.M., Siderovski, D.P., and Mak, T.W. (1998). Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29-39. https://doi.org/10.1016/S0092-8674(00)81780-8
  44. Thompson, B., Katsanis, N., Apostolopoulos, N., Thompson, D.C., Nebert, D.W., and Vasiliou, V. (2019). Genetics and functions of the retinoic acid pathway, with special emphasis on the eye. Hum. Genomics 13, 61. https://doi.org/10.1186/s40246-019-0248-9
  45. Tran, H., Brunet, A., Grenier, J.M., Datta, S.R., Fornace, A.J., Jr., DiStefano, P.S., Chiang, L.W., and Greenberg, M.E. (2002). DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530-534. https://doi.org/10.1126/science.1068712
  46. von Lintig, J. and Vogt, K. (2000). Filling the gap in vitamin A research. Molecular identification of an enzyme cleaving beta-carotene to retinal. J. Biol. Chem. 275, 11915-11920. https://doi.org/10.1074/jbc.275.16.11915
  47. Willbold, E., Rothermel, A., Tomlinson, S., and Layer, P.G. (2000). Muller glia cells reorganize reaggregating chicken retinal cells into correctly laminated in vitro retinae. Glia 29, 45-57. https://doi.org/10.1002/(SICI)1098-1136(20000101)29:1<45::AID-GLIA5>3.0.CO;2-4