Retina Metabolism and Metabolism in the Pigmented Epithelium: A Busy Intersection

Literature Cited

1. Acosta ML, Fletcher EL, Azizoglu S, Foster LE, Farber DB, Kalloniatis M. 2005. Early markers of retinal degeneration in rd/rd mice. Mol. Vis. 11:717–28
   [Google Scholar]
2. Adijanto J, Du J, Moffat C, Seifert EL, Hurley JB, Philp NJ. 2014. The retinal pigment epithelium utilizes fatty acids for ketogenesis. J. Biol. Chem. 289:20570–82
   [Google Scholar]
3. Aherne A, Kennan A, Kenna PF, McNally N, Lloyd DG et al. 2004. On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa. Hum. Mol. Genet. 13:641–50
   [Google Scholar]
4. Ait-Ali N, Fridlich R, Millet-Puel G, Clerin E, Delalande F et al. 2015. Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis. Cell 161:817–32
   [Google Scholar]
5. Ames A III, Li YY, Heher EC, Kimble CR. 1992. Energy metabolism of rabbit retina as related to function: high cost of Na⁺ transport. J. Neurosci. 12:840–53
   [Google Scholar]
6. Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M et al. 2020. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab 32:447–56.e6
   [Google Scholar]
7. Baik AH, Jain IH. 2020. Turning the oxygen dial: balancing the highs and lows. Trends Cell Biol 30:516–36
   [Google Scholar]
8. Bazan NG. 2018. Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection. Mol. Aspects Med. 64:18–33
   [Google Scholar]
9. Bisbach CM, Hass DT, Robbings BM, Rountree AM, Sadilek M et al. 2020a. Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium. Cell Rep 31:107606
   [Google Scholar]
10. Bisbach CM, Hutto RA, Poria D, Cleghorn WM, Abbas F et al. 2020b. Mitochondrial calcium uniporter (MCU) deficiency reveals an alternate path for Ca²⁺ uptake in photoreceptor mitochondria. Sci. Rep. 10:16041
    [Google Scholar]
11. Bowne SJ, Liu Q, Sullivan LS, Zhu J, Spellicy CJ et al. 2006. Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration?. Investig. Ophthalmol. Vis. Sci. 47:3754–65
    [Google Scholar]
12. Brown EE, Ball JD, Chen Z, Khurshid GS, Prosperi M, Ash JD. 2019a. The common antidiabetic drug metformin reduces odds of developing age-related macular degeneration. Investig. Ophthalmol. Vis. Sci. 60:1470–77
    [Google Scholar]
13. Brown EE, Lewin AS, Ash JD. 2019b. AMPK may play an important role in the retinal metabolic ecosystem. Adv. Exp. Med. Biol. 1185:477–81
    [Google Scholar]
14. Campochiaro PA, Iftikhar M, Hafiz G, Akhlaq A, Tsai G et al. 2020. Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial. J. Clin. Investig. 130:1527–41
    [Google Scholar]
15. Campochiaro PA, Mir TA. 2018. The mechanism of cone cell death in retinitis pigmentosa. Prog. Retin. Eye Res. 62:24–37
    [Google Scholar]
16. Caruso S, Ryu J, Quinn PM, Tsang SH. 2020. Precision metabolome reprogramming for imprecision therapeutics in retinitis pigmentosa. J. Clin. Investig. 130:3971–73
    [Google Scholar]
17. Casson RJ, Wood JP, Han G, Kittipassorn T, Peet DJ, Chidlow G. 2016. M-type pyruvate kinase isoforms and lactate dehydrogenase A in the mammalian retina: metabolic implications. Investig. Ophthalmol. Vis. Sci. 57:66–80
    [Google Scholar]
18. Chao JR, Knight K, Engel AL, Jankowski C, Wang Y et al. 2017. Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. J. Biol. Chem. 292:12895–905
    [Google Scholar]
19. Cheng SY, Cipi J, Ma S, Hafler BP, Kanadia RN et al. 2020. Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies. PNAS 117:13094–104
    [Google Scholar]
20. Chinchore Y, Begaj T, Wu D, Drokhlyansky E, Cepko CL. 2017. Glycolytic reliance promotes anabolism in photoreceptors. bioRxiv 101964. https://doi.org/10.1101/101964
    [Crossref]
21. Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H et al. 2010. Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol. Cell 38:487–99
    [Google Scholar]
22. Chowers G, Cohen M, Marks-Ohana D, Stika S, Eijzenberg A et al. 2017. Course of sodium iodate-induced retinal degeneration in albino and pigmented mice. Investig. Ophthalmol. Vis. Sci. 58:2239–49
    [Google Scholar]
23. Cohen LH, Noell WK. 1960. Glucose catabolism of rabbit retina before and after development of visual function. J. Neurochem. 5:253–76
    [Google Scholar]
24. Contreras L, Ramirez L, Du J, Hurley JB, Satrustegui J, de la, Villa P. 2016. Deficient glucose and glutamine metabolism in Aralar/AGC1/Slc25a12 knockout mice contributes to altered visual function. Mol. Vis. 22:1198–212
    [Google Scholar]
25. Curcio CA, Johnson M, Rudolf M, Huang JD 2011. The oil spill in ageing Bruch membrane. Br. J. Ophthalmol. 95:1638–45
    [Google Scholar]
26. Daniele LL, Caughey J, Volland S, Sharp RC, Dhingra A et al. 2019. Peroxisome turnover and diurnal modulation of antioxidant activity in retinal pigment epithelia utilizes microtubule-associated protein 1 light chain 3B (LC3B). Am. J. Physiol. Cell Physiol. 317:C1194–204
    [Google Scholar]
27. Dayton TL, Jacks T, Vander Heiden MG 2016. PKM2, cancer metabolism, and the road ahead. EMBO Rep 17:1721–30
    [Google Scholar]
28. Di Nardo A, Wertz MH, Kwiatkowski E, Tsai PT, Leech JD et al. 2014. Neuronal Tsc1/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum. Mol. Genet. 23:3865–74
    [Google Scholar]
29. Diaz-Garcia CM, Yellen G 2019. Neurons rely on glucose rather than astrocytic lactate during stimulation. J. Neurosci. Res. 97:883–89
    [Google Scholar]
30. DiCarlo JE, Mahajan VB, Tsang SH. 2018. Gene therapy and genome surgery in the retina. J. Clin. Investig. 128:2177–88
    [Google Scholar]
31. Du J, Cleghorn W, Contreras L, Linton JD, Chan GC et al. 2013. Cytosolic reducing power preserves glutamate in retina. PNAS 110:18501–6
    [Google Scholar]
32. Du J, Rountree A, Cleghorn WM, Contreras L, Lindsay KJ et al. 2016a. Phototransduction influences metabolic flux and nucleotide metabolism in mouse retina. J. Biol. Chem. 291:4698–710
    [Google Scholar]
33. Du J, Yanagida A, Knight K, Engel AL, Vo AH et al. 2016b. Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium. PNAS 113:14710–15
    [Google Scholar]
34. Du M, Mangold CA, Bixler GV, Brucklacher RM, Masser DR et al. 2017. Retinal gene expression responses to aging are sexually divergent. Mol. Vis. 23:707–17
    [Google Scholar]
35. Ebeling MC, Polanco JR, Qu J, Tu C, Montezuma SR, Ferrington DA. 2020. Improving retinal mitochondrial function as a treatment for age-related macular degeneration. Redox. Biol. 34:101552
    [Google Scholar]
36. Ershov AV, Bazan NG. 2000. Photoreceptor phagocytosis selectively activates PPARgamma expression in retinal pigment epithelial cells. J. Neurosci. Res. 60:328–37
    [Google Scholar]
37. Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C 2006. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging 27:983–93
    [Google Scholar]
38. Ferrington DA, Ebeling MC, Kapphahn RJ, Terluk MR, Fisher CR et al. 2017. Altered bioenergetics and enhanced resistance to oxidative stress in human retinal pigment epithelial cells from donors with age-related macular degeneration. Redox. Biol. 13:255–65
    [Google Scholar]
39. Ferrington DA, Fisher CR, Kowluru RA. 2020. Mitochondrial defects drive degenerative retinal diseases. Trends Mol. Med. 26:105–18
    [Google Scholar]
40. Findlay AS, Carter RN, Starbuck B, McKie L, Novakova K et al. 2018. Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function. Dis. Model. Mech. 11:dmm036426
    [Google Scholar]
41. Gantner ML, Eade K, Wallace M, Handzlik MK, Fallon R et al. 2019. Serine and lipid metabolism in macular disease and peripheral neuropathy. N. Engl. J. Med. 381:1422–33
    [Google Scholar]
42. Giarmarco MM, Cleghorn WM, Sloat SR, Hurley JB, Brockerhoff SE. 2017. Mitochondria maintain distinct Ca²⁺ pools in cone photoreceptors. J. Neurosci. 37:2061–72
    [Google Scholar]
43. Go YM, Zhang J, Fernandes J, Litwin C, Chen R et al. 2020. MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium. FASEB J 34:12502–20
    [Google Scholar]
44. Gospe SM III, Travis AM, Kolesnikov AV, Klingeborn M, Wang L et al. 2019. Photoreceptors in a mouse model of Leigh syndrome are capable of normal light-evoked signaling. J. Biol. Chem. 294:12432–43
    [Google Scholar]
45. Grenell A, Wang Y, Yam M, Swarup A, Dilan TL et al. 2019. Loss of MPC1 reprograms retinal metabolism to impair visual function. PNAS 116:3530–35
    [Google Scholar]
46. Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M et al. 2002. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat. Med. 8:718–24
    [Google Scholar]
47. Han JYS, Kinoshita J, Bisetto S, Bell BA, Nowak RA et al. 2020. Role of monocarboxylate transporters in regulating metabolic homeostasis in the outer retina: insight gained from cell-specific Bsg deletion. FASEB J 34:5401–19
    [Google Scholar]
48. Hanif AM, Lawson EC, Prunty M, Gogniat M, Aung MH et al. 2015. Neuroprotective effects of voluntary exercise in an inherited retinal degeneration mouse model. Investig. Ophthalmol. Vis. Sci. 56:6839–46
    [Google Scholar]
49. Hartong DT, Dange M, McGee TL, Berson EL, Dryja TP, Colman RF. 2008. Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nat. Genet. 40:1230–34
    [Google Scholar]
50. Hayasaka S, Hara S, Takaku Y, Mizuno K. 1977. Distribution of acid lipase in the bovine retinal pigment epithelium. Exp. Eye Res. 24:1–6
    [Google Scholar]
51. Hedstrom L. 2009. IMP dehydrogenase: structure, mechanism, and inhibition. Chem. Rev. 109:2903–28
    [Google Scholar]
52. Heng JS, Rattner A, Stein-O'Brien GL, Winer BL, Jones BW et al. 2019. Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution. PNAS 116:9103–14
    [Google Scholar]
53. Hu CA, Lin WW, Obie C, Valle D 1999. Molecular enzymology of mammalian Delta1-pyrroline-5-carboxylate synthase: Alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition. J. Biol. Chem. 274:6754–62
    [Google Scholar]
54. Huang J, Gu S, Chen M, Zhang SJ, Jiang Z et al. 2019. Abnormal mTORC1 signaling leads to retinal pigment epithelium degeneration. Theranostics 9:1170–80
    [Google Scholar]
55. Hue L, Taegtmeyer H. 2009. The Randle cycle revisited: a new head for an old hat. Am. J. Physiol. Endocrinol. Metab. 297:E578–91
    [Google Scholar]
56. Hurley JB, Lindsay KJ, Du J. 2015. Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J. Neurosci. Res. 93:1079–92
    [Google Scholar]
57. Hutto RA, Bisbach CM, Abbas F, Brock DC, Cleghorn WM et al. 2019. Increasing Ca²⁺ in photoreceptor mitochondria alters metabolites, accelerates photoresponse recovery, and reveals adaptations to mitochondrial stress. Cell Death Differ 27:1067–85
    [Google Scholar]
58. Ingram NT, Fain GL, Sampath AP 2020. Elevated energy requirement of cone photoreceptors. PNAS 117:19599–603
    [Google Scholar]
59. Itsara LS, Kennedy SR, Fox EJ, Yu S, Hewitt JJ et al. 2014. Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations. PLOS Genet 10:e1003974
    [Google Scholar]
60. Jain IH, Zazzeron L, Goldberger O, Marutani E, Wojtkiewicz GR et al. 2019. Leigh syndrome mouse model can be rescued by interventions that normalize brain hyperoxia, but not HIF activation. Cell Metab 30:824–32.e3
    [Google Scholar]
61. Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S et al. 2016. Hypoxia as a therapy for mitochondrial disease. Science 352:54–61
    [Google Scholar]
62. Jiang L, Shestov AA, Swain P, Yang C, Parker SJ et al. 2016. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532:255–58
    [Google Scholar]
63. Joyal JS, Gantner ML, Smith LEH. 2018. Retinal energy demands control vascular supply of the retina in development and disease: the role of neuronal lipid and glucose metabolism. Prog. Retin. Eye Res. 64:131–56
    [Google Scholar]
64. Kanow MA, Giarmarco MM, Jankowski CS, Tsantilas K, Engel AL et al. 2017. Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye. eLife 6:e28899
    [Google Scholar]
65. Kast B, Schori C, Grimm C. 2016. Hypoxic preconditioning protects photoreceptors against light damage independently of hypoxia inducible transcription factors in rods. Exp. Eye Res. 146:60–71
    [Google Scholar]
66. Keeling E, Chatelet DS, Tan NYT, Khan F, Richards R et al. 2020. 3D-reconstructed retinal pigment epithelial cells provide insights into the anatomy of the outer retina. Int. J. Mol. Sci. 21:8408
    [Google Scholar]
67. Kelley RA, Al-Ubaidi MR, Sinha T, Genc AM, Makia MS et al. 2017. Ablation of the riboflavin-binding protein retbindin reduces flavin levels and leads to progressive and dose-dependent degeneration of rods and cones. J. Biol. Chem. 292:21023–34
    [Google Scholar]
68. Kelly UL, Grigsby D, Cady MA, Landowski M, Skiba NP et al. 2020. High-density lipoproteins are a potential therapeutic target for age-related macular degeneration. J. Biol. Chem. 295:13601–16
    [Google Scholar]
69. Kim HJ, Zhao J, Sparrow JR 2020. Vitamin A aldehyde-taurine adduct and the visual cycle. PNAS 117:24867–75
    [Google Scholar]
70. Koch SF, Duong JK, Hsu CW, Tsai YT, Lin CS et al. 2017. Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa. PNAS 114:5259–64
    [Google Scholar]
71. Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I et al. 2012. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat. Genet. 44:1035–39
    [Google Scholar]
72. Kooragayala K, Gotoh N, Cogliati T, Nellissery J, Kaden TR et al. 2015. Quantification of oxygen consumption in retina ex vivo demonstrates limited reserve capacity of photoreceptor mitochondria. Investig. Ophthalmol. Vis. Sci. 56:8428–36
    [Google Scholar]
73. Kurihara T, Westenskow PD, Gantner ML, Usui Y, Schultz A et al. 2016. Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration. eLife 5:e14319
    [Google Scholar]
74. Lakkaraju A, Umapathy A, Tan LX, Daniele L, Philp NJ et al. 2021. The cell biology of the retinal pigment epithelium. Prog. Retin. Eye Res. In press
    [Google Scholar]
75. Lange C, Heynen SR, Tanimoto N, Thiersch M, Le YZ et al. 2011. Normoxic activation of hypoxia-inducible factors in photoreceptors provides transient protection against light-induced retinal degeneration. Investig. Ophthalmol. Vis. Sci. 52:5872–80
    [Google Scholar]
76. Lee SY, Usui S, Zafar AB, Oveson BC, Jo YJ et al. 2011. N-acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa. J. Cell Physiol. 226:1843–49
    [Google Scholar]
77. Leveillard T, Ait-Ali N. 2017. Cell signaling with extracellular thioredoxin and thioredoxin-like proteins: insight into their mechanisms of action. Oxid. Med. Cell Longev. 2017.8475125
    [Google Scholar]
78. Leveillard T, Philp NJ, Sennlaub F. 2019. Is retinal metabolic dysfunction at the center of the pathogenesis of age-related macular degeneration?. Int. J. Mol. Sci. 20:762
    [Google Scholar]
79. Li G, Anderson RE, Tomita H, Adler R, Liu X et al. 2007. Nonredundant role of Akt2 for neuroprotection of rod photoreceptor cells from light-induced cell death. J. Neurosci. 27:203–11
    [Google Scholar]
80. Lin H, Xu H, Liang FQ, Liang H, Gupta P et al. 2011. Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. Investig. Ophthalmol. Vis. Sci. 52:3521–29
    [Google Scholar]
81. Lin SC, Hardie DG. 2018. AMPK: sensing glucose as well as cellular energy status. Cell Metab 27:299–313
    [Google Scholar]
82. Lindsay KJ, Du J, Sloat SR, Contreras L, Linton JD et al. 2014. Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. PNAS 111:15579–84
    [Google Scholar]
83. Linsenmeier RA, Zhang HF. 2017. Retinal oxygen: from animals to humans. Prog. Retin. Eye Res. 58:115–51
    [Google Scholar]
84. Liu GY, Sabatini DM. 2020. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21:183–203
    [Google Scholar]
85. Magistretti PJ, Allaman I. 2018. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19:235–49
    [Google Scholar]
86. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE et al. 2004. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16:819–30
    [Google Scholar]
87. McDougald DS, Papp TE, Zezulin AU, Zhou S, Bennett J. 2019. AKT3 gene transfer promotes anabolic reprogramming and photoreceptor neuroprotection in a pre-clinical model of retinitis pigmentosa. Mol. Ther. 27:1313–26
    [Google Scholar]
88. Mees LM, Coulter MM, Chrenek MA, Motz CT, Landis EG et al. 2019. Low-intensity exercise in mice is sufficient to protect retinal function during light-induced retinal degeneration. Investig. Ophthalmol. Vis. Sci. 60:1328–35
    [Google Scholar]
89. Meschede IP, Ovenden NC, Seabra MC, Futter CE, Votruba M et al. 2020. Symmetric arrangement of mitochondria:plasma membrane contacts between adjacent photoreceptor cells regulated by Opa1. PNAS 117:15684–93
    [Google Scholar]
90. Mihaylova MM, Shaw RJ. 2011. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13:1016–23
    [Google Scholar]
91. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S et al. 2016. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806
    [Google Scholar]
92. O'Donnell JJ, Sandman RP, Martin SR. 1978. Gyrate atrophy of the retina: inborn error of L-ornithin:2-oxoacid aminotransferase. Science 200:200–1
    [Google Scholar]
93. Okawa H, Sampath AP, Laughlin SB, Fain GL. 2008. ATP consumption by mammalian rod photoreceptors in darkness and in light. Curr. Biol. 18:1917–21
    [Google Scholar]
94. Pan WW, Wubben TJ, Besirli CG. 2021. Photoreceptor metabolic reprogramming: current understanding and therapeutic implications. Commun. Biol. 4:425
    [Google Scholar]
95. Petit L, Ma S, Cipi J, Cheng SY, Zieger M et al. 2018. Aerobic glycolysis is essential for normal rod function and controls secondary cone death in retinitis pigmentosa. Cell Rep 23:2629–42
    [Google Scholar]
96. Philp NJ, Yoon H, Grollman EF. 1998. Monocarboxylate transporter MCT1 is located in the apical membrane and MCT3 in the basal membrane of rat RPE. Am. J. Physiol. 274:R1824–28
    [Google Scholar]
97. Philp NJ, Yoon H, Lombardi L. 2001. Mouse MCT3 gene is expressed preferentially in retinal pigment and choroid plexus epithelia. Am. J. Physiol. Cell Physiol. 280:C1319–26
    [Google Scholar]
98. Plana-Bonamaiso A, Lopez-Begines S, Fernandez-Justel D, Junza A, Soler-Tapia A et al. 2020. Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions. eLife 9:e56418
    [Google Scholar]
99. Poitry-Yamate CL, Poitry S, Tsacopoulos M. 1995. Lactate released by Muller glial cells is metabolized by photoreceptors from mammalian retina. J. Neurosci. 15:5179–91
    [Google Scholar]
100. Prag HA, Gruszczyk AV, Huang MM, Beach TE, Young T et al. 2021. Mechanism of succinate efflux upon reperfusion of the ischemic heart. Cardiovasc. Res. 117:41188–201
     [Google Scholar]
101. Punzo C, Kornacker K, Cepko CL. 2009. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat. Neurosci. 12:44–52
     [Google Scholar]
102. Punzo C, Xiong W, Cepko CL. 2012. Loss of daylight vision in retinal degeneration: Are oxidative stress and metabolic dysregulation to blame?. J. Biol. Chem. 287:1642–48
     [Google Scholar]
103. Rajala A, Gupta VK, Anderson RE, Rajala RV. 2013. Light activation of the insulin receptor regulates mitochondrial hexokinase: a possible mechanism of retinal neuroprotection. Mitochondrion 13:566–76
     [Google Scholar]
104. Rajala A, Wang Y, Brush RS, Tsantilas K, Jankowski CSR et al. 2018a. Pyruvate kinase M2 regulates photoreceptor structure, function, and viability. Cell Death Dis 9:240
     [Google Scholar]
105. Rajala A, Wang Y, Rajala RVS. 2018b. Constitutive activation mutant mTOR promote cone survival in retinitis pigmentosa mice. Adv. Exp. Med. Biol. 1074:491–97
     [Google Scholar]
106. Rajala A, Wang Y, Soni K, Rajala RVS. 2018c. Pyruvate kinase M2 isoform deletion in cone photoreceptors results in age-related cone degeneration. Cell Death Dis 9:737
     [Google Scholar]
107. Rajala RV, Rajala A, Kooker C, Wang Y, Anderson RE. 2016. The Warburg effect mediator pyruvate kinase M2 expression and regulation in the retina. Sci. Rep 6:37727
     [Google Scholar]
108. Randle PJ, Garland PB, Hales CN, Newsholme EA. 1963. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–89
     [Google Scholar]
109. Reidel B, Thompson JW, Farsiu S, Moseley MA, Skiba NP, Arshavsky VY. 2011. Proteomic profiling of a layered tissue reveals unique glycolytic specializations of photoreceptor cells. Mol. Cell Proteom. 10:M110.002469
     [Google Scholar]
110. Reyes-Reveles J, Dhingra A, Alexander D, Bragin A, Philp NJ, Boesze-Battaglia K. 2017. Phagocytosis-dependent ketogenesis in retinal pigment epithelium. J. Biol. Chem. 292:8038–47
     [Google Scholar]
111. Rohrer B, Bandyopadhyay M, Beeson C. 2016. Reduced metabolic capacity in aged primary retinal pigment epithelium (RPE) is correlated with increased susceptibility to oxidative stress. Adv. Exp. Med. Biol. 854:793–98
     [Google Scholar]
112. Rosales MAB, Shu DY, Iacovelli J, Saint-Geniez M. 2019. Loss of PGC-1α in RPE induces mesenchymal transition and promotes retinal degeneration. Life Sci. Alliance 2:e201800212
     [Google Scholar]
113. Rowan S, Jiang S, Chang ML, Volkin J, Cassalman C et al. 2020. A low glycemic diet protects disease-prone Nrf2-deficient mice against age-related macular degeneration. Free Radic. Biol. Med. 150:75–86
     [Google Scholar]
114. Rowan S, Taylor A. 2018. The role of microbiota in retinal disease. Adv. Exp. Med. Biol. 1074:429–35
     [Google Scholar]
115. Rueda EM, Johnson JE Jr., Giddabasappa A, Swaroop A, Brooks MJ et al. 2016. The cellular and compartmental profile of mouse retinal glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and ∼P transferring kinases. Mol. Vis. 22:847–85
     [Google Scholar]
116. Ruggiero L, Connor MP, Chen J, Langen R, Finnemann SC 2012. Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5-/- or Mfge8-/- mouse retina. PNAS 109:8145–48
     [Google Scholar]
117. Samardzija M, Barben M, Todorova V, Klee K, Storti F, Grimm C 2019. Hif1a and Hif2a can be safely inactivated in cone photoreceptors. Sci. Rep. 9:16121
     [Google Scholar]
118. Sasaki Y, Kakita H, Kubota S, Sene A, Lee TJ et al. 2020. SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration. eLife 9:e62027
     [Google Scholar]
119. Scerri TS, Quaglieri A, Cai C, Zernant J, Matsunami N et al. 2017. Genome-wide analyses identify common variants associated with macular telangiectasia type 2. Nat. Genet. 49:559–67
     [Google Scholar]
120. Semenza GL. 2011. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365:537–47
     [Google Scholar]
121. Senanayake P, Calabro A, Hu JG, Bonilha VL, Darr A et al. 2006. Glucose utilization by the retinal pigment epithelium: evidence for rapid uptake and storage in glycogen, followed by glycogen utilization. Exp. Eye Res. 83:235–46
     [Google Scholar]
122. Shen J, Yang X, Dong A, Petters RM, Peng YW et al. 2005. Oxidative damage is a potential cause of cone cell death in retinitis pigmentosa. J. Cell Physiol. 203:457–64
     [Google Scholar]
123. Shu W, Dunaief JL. 2018. Potential treatment of retinal diseases with iron chelators. Pharmaceuticals 11:112
     [Google Scholar]
124. Simell O, Takki K. 1973. Raised plasma-ornithine and gyrate atrophy of the choroid and retina. Lancet 1:1031–33
     [Google Scholar]
125. Sinha T, Du J, Makia MS, Hurley JB, Naash MI, Al-Ubaidi MR 2021. Absence of retbindin blocks glycolytic flux, disrupts metabolic homeostasis, and leads to photoreceptor degeneration. PNAS 118:e2018956118
     [Google Scholar]
126. Sinha T, Makia M, Du J, Naash MI, Al-Ubaidi MR. 2018. Flavin homeostasis in the mouse retina during aging and degeneration. J. Nutr. Biochem. 62:123–33
     [Google Scholar]
127. Sinha T, Naash MI, Al-Ubaidi MR 2020a. Flavins act as a critical liaison between metabolic homeostasis and oxidative stress in the retina. Front. . Cell Dev. Biol. 8:861
     [Google Scholar]
128. Sinha T, Naash MI, Al-Ubaidi MR 2020b. The symbiotic relationship between the neural retina and retinal pigment epithelium is supported by utilizing differential metabolic pathways. iScience 23:101004
     [Google Scholar]
129. Stone J, van Driel D, Valter K, Rees S, Provis J 2008. The locations of mitochondria in mammalian photoreceptors: relation to retinal vasculature. Brain Res 1189:58–69
     [Google Scholar]
130. Swarup A, Samuels IS, Bell BA, Han JYS, Du J et al. 2018. Modulating GLUT1 expression in the RPE decreases glucose levels in the retina: impact on photoreceptors and Muller glial cells. Am. J. Physiol. Cell Physiol. 316:C121–33
     [Google Scholar]
131. Terluk MR, Kapphahn RJ, Soukup LM, Gong H, Gallardo C et al. 2015. Investigating mitochondria as a target for treating age-related macular degeneration. J. Neurosci. 35:7304–11
     [Google Scholar]
132. Thiersch M, Lange C, Joly S, Heynen S, Le YZ et al. 2009. Retinal neuroprotection by hypoxic preconditioning is independent of hypoxia-inducible factor-1 alpha expression in photoreceptors. Eur. J. Neurosci. 29:2291–302
     [Google Scholar]
133. Tyni T, Johnson M, Eaton S, Pourfarzam M, Andrews R, Turnbull DM. 2002. Mitochondrial fatty acid beta-oxidation in the retinal pigment epithelium. Pediatr. Res. 52:595–600
     [Google Scholar]
134. Ueda K, Kim HJ, Zhao J, Song Y, Dunaief JL, Sparrow JR 2018. Iron promotes oxidative cell death caused by bisretinoids of retina. PNAS 115:4963–68
     [Google Scholar]
135. Ueda M, Masu Y, Ando A, Maeda H, Del Monte MA et al. 1998. Prevention of ornithine cytotoxicity by proline in human retinal pigment epithelial cells. Investig. Ophthalmol. Vis. Sci. 39:820–27
     [Google Scholar]
136. Venkatesh A, Ma S, Le YZ, Hall MN, Ruegg MA, Punzo C. 2015. Activated mTORC1 promotes long-term cone survival in retinitis pigmentosa mice. J. Clin. Investig. 125:1446–58
     [Google Scholar]
137. Vijayasarathy C, Damle S, Prabu SK, Otto CM, Avadhani NG. 2003. Adaptive changes in the expression of nuclear and mitochondrial encoded subunits of cytochrome c oxidase and the catalytic activity during hypoxia. Eur. J. Biochem. 270:871–79
     [Google Scholar]
138. Vlachantoni D, Bramall AN, Murphy MP, Taylor RW, Shu X et al. 2011. Evidence of severe mitochondrial oxidative stress and a protective effect of low oxygen in mouse models of inherited photoreceptor degeneration. Hum. Mol. Genet. 20:322–35
     [Google Scholar]
139. Vohra R, Kolko M. 2020. Lactate: more than merely a metabolic waste product in the inner retina. Mol. Neurobiol. 57:2021–37
     [Google Scholar]
140. Wang L, Tornquist P, Bill A. 1997a. Glucose metabolism in pig outer retina in light and darkness. Acta Physiol. Scand. 160:75–81
     [Google Scholar]
141. Wang L, Tornquist P, Bill A. 1997b. Glucose metabolism of the inner retina in pigs in darkness and light. Acta Physiol. Scand. 160:71–74
     [Google Scholar]
142. Wang W, Kini A, Wang Y, Liu T, Chen Y et al. 2019. Metabolic deregulation of the blood-outer retinal barrier in retinitis pigmentosa. Cell Rep 28:1323–34.e4
     [Google Scholar]
143. Wang W, Lee SJ, Scott PA, Lu X, Emery D et al. 2016. Two-step reactivation of dormant cones in retinitis pigmentosa. Cell Rep 15:372–85
     [Google Scholar]
144. Wang Y, Grenell A, Zhong F, Yam M, Hauer A et al. 2018. Metabolic signature of the aging eye in mice. Neurobiol. Aging 71:223–33
     [Google Scholar]
145. Warburg O, Posener K, Negrelein E. 1924. On the metabolism of carcinoma cells. Biochem. Z. 152:309–44
     [Google Scholar]
146. Weh E, Lutrzykowska Z, Smith A, Hager H, Pawar M et al. 2020. Hexokinase 2 is dispensable for photoreceptor development but is required for survival during aging and outer retinal stress. Cell Death Dis 11:422
     [Google Scholar]
147. Weiss ER, Osawa S, Xiong Y, Dhungana S, Carlson J et al. 2019. Broad spectrum metabolomics for detection of abnormal metabolic pathways in a mouse model for retinitis pigmentosa. Exp. Eye Res. 184:135–45
     [Google Scholar]
148. Wert KJ, Velez G, Kanchustambham VL, Shankar V, Evans LP et al. 2020. Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration. EBioMedicine 52:102636
     [Google Scholar]
149. Williams PA, Harder JM, Foxworth NE, Cochran KE, Philip VM et al. 2017. Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355:756–60
     [Google Scholar]
150. Winkler BS. 1981. Glycolytic and oxidative metabolism in relation to retinal function. J. Gen. Physiol. 77:667–92
     [Google Scholar]
151. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ et al. 2011. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. PNAS 108:19611–16
     [Google Scholar]
152. Wohl SG, Reh TA. 2016. The microRNA expression profile of mouse Muller glia in vivo and in vitro. Sci. Rep. 6:35423
     [Google Scholar]
153. Wolf A, Agnihotri S, Micallef J, Mukherjee J, Sabha N et al. 2011. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med. 208:313–26
     [Google Scholar]
154. Wubben TJ, Pawar M, Smith A, Toolan K, Hager H, Besirli CG. 2017. Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration. Sci. Rep. 7:17863
     [Google Scholar]
155. Wubben TJ, Pawar M, Weh E, Smith A, Sajjakulnukit P et al. 2020. Small molecule activation of metabolic enzyme pyruvate kinase muscle isozyme 2, PKM2, circumvents photoreceptor apoptosis. Sci. Rep. 10:2990
     [Google Scholar]
156. Xu L, Brown EE, Keuthan CJ, Gubbi H, Grellier E-K, Roger J et al. 2020. AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE. bioRxiv 109165. https://doi.org/10.1101/2020.05.22.109165
     [Crossref]
157. Xu L, Kong L, Wang J, Ash JD 2018. Stimulation of AMPK prevents degeneration of photoreceptors and the retinal pigment epithelium. PNAS 115:10475–80
     [Google Scholar]
158. Xu R, Ritz BK, Wang Y, Huang J, Zhao C et al. 2020. The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected. J. Biol. Chem. 295:2324–35
     [Google Scholar]
159. Xu Y, Ola MS, Berkich DA, Gardner TW, Barber AJ et al. 2007. Energy sources for glutamate neurotransmission in the retina: absence of the aspartate/glutamate carrier produces reliance on glycolysis in glia. J. Neurochem. 101:120–31
     [Google Scholar]
160. Yam M, Engel AL, Wang Y, Zhu S, Hauer A et al. 2019. Proline mediates metabolic communication between retinal pigment epithelial cells and the retina. J. Biol. Chem. 294:10278–89
     [Google Scholar]
161. Yu DY, Cringle SJ. 2005. Retinal degeneration and local oxygen metabolism. Exp. Eye Res. 80:745–51
     [Google Scholar]
162. Yuan Z, Li B, Xu M, Chang EY, Li H et al. 2017. The phenotypic variability of HK1-associated retinal dystrophy. Sci. Rep. 7:7051
     [Google Scholar]
163. Zhang E, Ryu J, Levi SR, Oh JK, Hsu CW et al. 2020. PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa. Mamm. Genome 31:77–85
     [Google Scholar]
164. Zhang L, Du J, Justus S, Hsu CW, Bonet-Ponce L et al. 2016a. Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. J. Clin. Investig. 126:4659–73
     [Google Scholar]
165. Zhang L, Justus S, Xu Y, Pluchenik T, Hsu CW et al. 2016b. Reprogramming towards anabolism impedes degeneration in a preclinical model of retinitis pigmentosa. Hum. Mol. Genet. 25:4244–55
     [Google Scholar]
166. Zhang M, Chu Y, Mowery J, Konkel B, Galli S et al. 2018. Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice. Dis. Model. Mech. 11:dmm032698
     [Google Scholar]
167. Zhang R, Shen W, Du J, Gillies MC. 2020. Selective knockdown of hexokinase 2 in rods leads to age-related photoreceptor degeneration and retinal metabolic remodeling. Cell Death Differ 11:885
     [Google Scholar]
168. Zhang X, Girardot PE, Sellers JT, Li Y, Wang J et al. 2019. Wheel running exercise protects against retinal degeneration in the I307N rhodopsin mouse model of inducible autosomal dominant retinitis pigmentosa. Mol. Vis. 25:462–76
     [Google Scholar]
169. Zhang X, Henneman NF, Girardot PE, Sellers JT, Chrenek MA et al. 2020. Systemic treatment with nicotinamide riboside is protective in a mouse model of light-induced retinal degeneration. Investig. Ophthalmol. Vis. Sci. 61:47
     [Google Scholar]
170. Zhao C, Yasumura D, Li X, Matthes M, Lloyd M et al. 2011. mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice. J. Clin. Investig. 121:369–83
     [Google Scholar]
171. Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE et al. 2010. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280–93
     [Google Scholar]
172. Zimmerman WF, Godchaux W III, Belkin M. 1983. The relative proportions of lysosomal enzyme activities in bovine retinal pigment epithelium. Exp. Eye Res. 36:151–58
     [Google Scholar]