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Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye
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Abstract
Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.
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“In contrast, the RPE is oxidative and uses lactate produced by the photoreceptors and fatty acids from ingested OSs to fuel mitochondrial metabolism (Adijanto et al., 2014; Adijanto and Philp, 2014; Kanow et al., 2017; Reyes-Reveles et al., 2017).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kanow et al., 2017
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“the opposite appears to be true: photoreceptors perform aerobic glycolysis and export lactate, which is then oxidized by Müller cells (Hurley et al., 2015; Kanow et al., 2017).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Kanow et al., 2017
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Cites
Tissue-based map of the human proteome
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015) · Science · doi:10.1126/science.1260419 · Cited by 15,286
Prevalence of Age-Related Macular Degeneration in the United States
The Eye Diseases Prevalence Research Group* (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.564 · Cited by 2,774
The Metabolism of Carcinoma Cells
Warburg, O. H. (1925) · The Journal of Cancer Research · doi:10.1158/jcr.1925.148 · Cited by 1,005
Curcio, C. A., Millican, C. L., Allen, K. A., & Kalina, R. E. (1993) · PubMed · Cited by 678
Mattapallil, M. J., Wawrousek, E. F., Chan, C.-C., Zhao, H., Roychoudhury, J., Ferguson, T. A., & Caspi, R. R. (2012) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.12-9662 · Cited by 678
Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa
Punzo, C., Kornacker, K., & Cepko, C. L. (2008) · Nature Neuroscience · doi:10.1038/nn.2234 · Cited by 515
Imaging cytosolic NADH-NAD(+) redox state with a genetically encoded fluorescent biosensor
Hung, Y. P., Albeck, J. G., Tantama, M., & Yellen, G. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.012 · Cited by 509
Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis
Aït-Ali, N., Fridlich, R., Millet-Puel, G., Clérin, E., Delalande, F., Jaillard, C., Blond, F., Perrocheau, L., Reichman, S., Byrne, L. C., et al. (2015) · Cell · doi:10.1016/j.cell.2015.03.023 · Cited by 423
Glycolytic and oxidative metabolism in relation to retinal function.
Winkler, B. S. (1981) · The Journal of General Physiology · doi:10.1085/jgp.77.6.667 · Cited by 376
Akimoto, M., Cheng, H., Zhu, D., Brzezinski, J. A., Khanna, R., Filippova, E. V., Oh, E. C. T., Jing, Y., Linares, J., Brooks, M., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508214103 · Cited by 321
Zhao, C., Yasumura, D., Li, X., Matthes, M., Lloyd, M., Nielsen, G., Ahern, K., Snyder, M., Bok, D., Dunaief, J. L., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44303 · Cited by 303
Evaluation of 13C isotopic tracers for metabolic flux analysis in mammalian cells
Metallo, C. M., Walther, J. L., & Stephanopoulos, G. (2009) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2009.07.010 · Cited by 280
Müller cell localisation of glutamine synthetase in rat retina
Riepe, R. E., & NORENBURG, M. D. (1977) · Nature · doi:10.1038/268654a0 · Cited by 277
Glucose, lactate, and shuttling of metabolites in vertebrate retinas
Hurley, J. B., Lindsay, K. J., & Du, J. (2015) · Journal of Neuroscience Research · doi:10.1002/jnr.23583 · Cited by 275
Sonoda, S., Spee, C., Barron, E., Ryan, S. J., Kannan, R., & Hinton, D. R. (2009) · Nature Protocols · doi:10.1038/nprot.2009.33 · Cited by 272
Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1
Joyal, J., Sun, Y., Gantner, M. L., Shao, Z., Evans, L. P., Saba, N., Fredrick, T. W., Burnim, S. B., Kim, J. S., Patel, G., et al. (2016) · Nature Medicine · doi:10.1038/nm.4059 · Cited by 266
Investigating Mitochondria as a Target for Treating Age-Related Macular Degeneration
Terluk, M. R., Kapphahn, R. J., Soukup, L. M., Gong, H., Gallardo, C., Montezuma, S. R., & Ferrington, D. A. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0190-15.2015 · Cited by 253
Human Retinal Pigment Epithelium Cells as Functional Models for the RPE In Vivo
Ablonczy, Z., Dahrouj, M., Tang, P. H., Liu, Y., Sambamurti, K., Marmorstein, A. D., & Crosson, C. E. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-8021 · Cited by 243
Yoshioka, K., Takahashi, H., Homma, T., Saito, M., Oh, K., Nemoto, Y., & Matsuoka, H. (1996) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(95)00153-0 · Cited by 242
Kurihara, T., Westenskow, P. D., Gantner, M. L., Usui, Y., Schultz, A. W., Bravo, S., Aguilar, E., Wittgrove, C. M., Friedlander, M. S. H., Paris, L. P., et al. (2016) · eLife · doi:10.7554/elife.14319 · Cited by 221
Normal-Range Blood Lactate Concentration in Septic Shock Is Prognostic and Predictive
Wacharasint, P., Nakada, T., Boyd, J. H., Russell, J. A., & Walley, K. R. (2012) · Shock · doi:10.1097/shk.0b013e318254d41a · Cited by 220
Johnson, L. V., Forest, D. L., Banna, C. D., Radeke, C. M., Maloney, M. A., Hu, J. G., Spencer, C. N., Walker, A. M., Tsie, M. S., Bok, D., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109703108 · Cited by 196
Glycolytic reliance promotes anabolism in photoreceptors
Chinchore, Y., Begaj, T., Wu, D., Drokhlyansky, E., & Cepko, C. L. (2017) · eLife · doi:10.7554/elife.25946 · Cited by 191
Punzo, C., Xiong, W., & Cepko, C. L. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.304428 · Cited by 185
The Retinal Pigment Epithelium Utilizes Fatty Acids for Ketogenesis
Adijanto, J., Du, J., Moffat, C., Seifert, E. L., Hurley, J. B., & Philp, N. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.565457 · Cited by 176
Matschinsky, F. M., Passonneau, J. V., & Lowry, O. H. (1968) · Journal of Histochemistry & Cytochemistry · doi:10.1177/16.1.29 · Cited by 162
Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice
Venkatesh, A., Ma, S., Le, Y. Z., Hall, M. N., Rüegg, M. A., & Punzo, C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci79766 · Cited by 158
Bramall, A. N., Wright, A. F., Jacobson, S. G., & McInnes, R. R. (2010) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153227 · Cited by 151
Efficient homologous recombination-mediated genome engineering in zebrafish using TALE nucleases
Shin, J., Chen, J., & Solnica‐Krezel, L. (2014) · Development · doi:10.1242/dev.108019 · Cited by 135
Lindsay, K. J., Du, J., Sloat, S. R., Contreras, L., Linton, J. D., Turner, S. J., Sadilek, M., Satrústegui, J., & Hurley, J. B. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412441111 · Cited by 131
Medrano, C. J., & Fox, D. A. (1995) · Experimental Eye Research · doi:10.1016/s0014-4835(05)80122-8 · Cited by 125
Plasma membrane protein polarity and trafficking in RPE cells: past, present and future
Lehmann, G. L., Benedicto, I., Philp, N. J., & Rodriguez-Boulan, E. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.04.021 · Cited by 122
Flow of energy in the outer retina in darkness and in light
Linton, J. D., Holzhausen, L. C., Babai, N. Z., Song, H., Miyagishima, K. J., Stearns, G., Lindsay, K. J., Wei, J., Chertov, A. O., Peters, T. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002471107 · Cited by 119
Whitmore, S. S., Wagner, A. H., DeLuca, A. P., Drack, A. V., Stone, E. M., Tucker, B. A., Zeng, S., Braun, T. A., Mullins, R. F., & Scheetz, T. E. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.11.001 · Cited by 117
Phagocytosis-dependent ketogenesis in retinal pigment epithelium
Reyes-Reveles, J., Dhingra, A., Alexander, D., Bragin, A., Philp, N. J., & Boesze-Battaglia, K. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.770784 · Cited by 116
Glucose metabolism in pig outer retina in light and darkness
Wang, L., Törnquist, P., & Bill, A. (1997) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.1997.00131.x · Cited by 115
Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium
Du, J., Yanagida, A., Knight, K., Engel, A. L., Vo, A. H., Jankowski, C. S. R., Sadı́lek, M., Tran, V., Manson, M. A., Ramakrishnan, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604572113 · Cited by 115
Badr, G., Tang, J., Ismail-Beigi, F., & Kern, T. S. (2000) · Diabetes · doi:10.2337/diabetes.49.6.1016 · Cited by 113
Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa
Wang, W., Lee, S. J., Scott, P. A., Lu, X., Emery, D., Liu, Y., Ezashi, T., Roberts, M. R., Ross, J. W., Kaplan, H. J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.022 · Cited by 105
Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration
Zhang, L., Du, J., Justus, S., Hsu, C., Bonet‐Ponce, L., Wu, W.-H., Tsai, Y.-T., Wu, W., Jia, Y., Duong, J., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci86905 · Cited by 102
Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina
Du, J., Rountree, A. M., Cleghorn, W. M., Contreras, L., Lindsay, K. J., Sadı́lek, M., Gu, H., Djukovic, D., Raftery, D., Satrústegui, J., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.698985 · Cited by 97
Chao, J. R., Knight, K., Engel, A. L., Jankowski, C. S. R., Wang, Y., Manson, M. A., Gu, H., Djukovic, D., Raftery, D., Hurley, J. B., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.788422 · Cited by 93
Blenkinsop, T. A., Saini, J. S., Maminishkis, A., Bharti, K., Wan, Q., Banzon, T. M., Lotfi, M., Davis, J. A., Singh, D., Rizzolo, L. J., et al. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-16246 · Cited by 87
Du, J., Cleghorn, W. M., Contreras, L., Lindsay, K. J., Rountree, A. M., Chertov, A. O., Turner, S. J., Sahaboglu, A., Linton, J., Sadı́lek, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.507285 · Cited by 86
Collymore, C., Rasmussen, S., & Tolwani, R. J. (2013) · Journal of Visualized Experiments · doi:10.3791/50691 · Cited by 80
Rueda, E. M., Johnson, J. E., Giddabasappa, A., Swaroop, A., Brooks, M. J., Sigel, I., Chaney, S. Y., & Fox, D. A. (2016) · PubMed Central · Cited by 78
Adijanto, J., & Philp, N. J. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.01.015 · Cited by 73
Probing Metabolism in the Intact Retina Using Stable Isotope Tracers
Du, J., Linton, J. D., & Hurley, J. B. (2015) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2015.04.002 · Cited by 71
The Warburg Effect Mediator Pyruvate Kinase M2 Expression and Regulation in the Retina
Rajala, R. V. S., Rajala, A., Kooker, C., Wang, Y., & Anderson, R. E. (2016) · Scientific Reports · doi:10.1038/srep37727 · Cited by 66
Cytosolic reducing power preserves glutamate in retina
Du, J., Cleghorn, W. M., Contreras, L., Linton, J. D., Chan, G. C. ‐., Chertov, A. O., Saheki, T., Govindaraju, V., Sadı́lek, M., Satrústegui, J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311193110 · Cited by 62
Facilitative glucose transporter Glut1 is actively excluded from rod outer segments
Gospe, S. M., Baker, S. A., & Arshavsky, V. Y. (2010) · Journal of Cell Science · doi:10.1242/jcs.072389 · Cited by 60
The microRNA expression profile of mouse Müller glia in vivo and in vitro
Wohl, S. G., & Reh, T. A. (2016) · Scientific Reports · doi:10.1038/srep35423 · Cited by 60
Senanayake, P. D., Calabro, A. R., Hu, J. G., Bonilha, V. L., Darr, A., Bok, D., & Hollyfield, J. G. (2006) · Experimental Eye Research · doi:10.1016/j.exer.2005.10.034 · Cited by 57
Casson, R. J., Wood, J. P. M., Han, G., Kittipassorn, T., Peet, D. J., & Chidlow, G. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17962 · Cited by 56
Santos, L. R. B., Muller, C., de Souza, A. H., Takahashi, H., Spégel, P., Sweet, I. R., Chae, H., Mulder, H., & Jonas, J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.04.004 · Cited by 50
Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease
Kolko, M., Vosborg, F., Henriksen, U. L., Hasan‐Olive, M. M., Diget, E. H., Vohra, R., Gurubaran, I. S., GJEDDE, A. H., Mariga, S. T., Skytt, D. M., et al. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1792-x · Cited by 49
Ea, B., & Sylvén, B. (1962) · PubMed · Cited by 48
An easy, rapid method to isolate RPE cell protein from the mouse eye
Wei, H., Xun, Z., Granado, H., Wu, A., & Handa, J. T. (2015) · Experimental Eye Research · doi:10.1016/j.exer.2015.09.015 · Cited by 47
Mitochondria Maintain Distinct Ca 2+ Pools in Cone Photoreceptors
Giarmarco, M. M., Cleghorn, W. M., Sloat, S. R., Hurley, J. B., & Brockerhoff, S. E. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.2689-16.2017 · Cited by 44
Raymond, P. A., Colvin, S. M., Jabeen, Z., Nagashima, M., Barthel, L. K., Hadidjojo, J., Popova, L., Pejaver, V. R., & Lubensky, D. K. (2014) · PLoS ONE · doi:10.1371/journal.pone.0085325 · Cited by 43
Jung, S., Reed, B. J., & Sweet, I. R. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00282.2009 · Cited by 43
Correction of Monogenic and Common Retinal Disorders with Gene Therapy
Sengillo, J. D., Justus, S., Cabral, T., & Tsang, S. H. (2017) · Genes · doi:10.3390/genes8020053 · Cited by 39
Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa
Koch, S., Duong, J., Hsu, C., Tsai, Y.-T., Lin, C., Wahl‐Schott, C., & Tsang, S. H. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615394114 · Cited by 31
Wild-Type Cone Photoreceptors Persist Despite Neighboring Mutant Cone Degeneration
Lewis, A. A., Williams, P. R., Lawrence, O. T., Wong, R., & Brockerhoff, S. E. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.5019-09.2010 · Cited by 24
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- Krebs, 1927, On the metabolism of the retina, Biochemische Zeitschrift, 189, 57
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Metadata
- Authors
- Kanow, M. A., Giarmarco, M. M., Jankowski, C. S., Tsantilas, K., Engel, A. L., Du, J., Linton, J. D., Farnsworth, C. C., Sloat, S. R., Rountree, A., Sweet, I. R., Lindsay, K. J., Parker, E. D., Brockerhoff, S. E., Sadilek, M., Chao, J. R., & Hurley, J. B.
- Affiliations
- University of Washington (US)
- West Virginia University (US)
- Department of Chemistry, University of Washington, Seattle, United States
- Corresponding author
- Hurley, James B
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2017-09-13
- Volume
- 6
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5617631
- OpenAlex
- W2617421506
- Cited by
- 377
- References
- 64
- Citations by year
- 2026: 44 · 2025: 36 · 2024: 59 · 2023: 48 · 2022: 48 · 2021: 53 · 2020: 48 · 2019: 23 · 2018: 15 · 2017: 2
- FWCI
- 9.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Research Repository @ WVU (West Virginia University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (GRFP 2013158531)
- National Eye Institute (5T32EY007031, EY026030, EY026020, EY06641, EY017863, EY001730)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 17047)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- retinal metabolism, retinal pigment epithelium, photoreceptors, lactate, glucose metabolism, Müller cells, choroid, metabolic flux, age-related vision loss, retinal disease, mice, zebrafish
- MeSH terms
- Adaptation, Ocular, Animals, Energy Metabolism, Glucose, Humans, Lactates, Photoreceptor Cells, Zebrafish, Mice, Retinal Pigment Epithelium, Ependymoglial Cells
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