Research progress on the role and mechanism of lactate in retinal diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Gao Yan , Mao Xiying , Chen Mingkang , Yuan Songtao ,  Liu Qinghuai

Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 210029, China;

Corresponding author：

Liu Qinghuai, Email: liuqh@njmu.edu.cn

Keywords：

Lactate; Retinal neovasculature; Retinal inflammation; Lactylation; Review

DOI：

10.3760/cma.j.cn511434-20240731-00292

Video：

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Abstract Full text Figures/Tables Video References Cited by

Lactate was originally thought to be a metabolic waste product of glycolysis produced by cells in hypoxic environment. In recent years, increasing evidence has indicated that lactate plays a crucial role in the physiological and pathological processes of the retina. Lactate is transported via monocarboxylate transporters in different retinal cell types such as photoreceptor cells and Müller cells to maintain the high metabolic demand of the retina. In addition to serving as oxiditive substrate for energy, lactate can mediate intracellular signal transduction through receptor G protein-coupled receptor 81, participating in the maintenance of retinal homeostasis and the progression of pathological neovascularization. Moreover, lactate-mediated protein lactylation directly regulates gene expression in microglia and T lymphocytes, which has gradually become a new hotspot in the field of retinal pathological neovascularization and neuroinflammation. Therefore, the regulation of lactate metabolism may provide novel perspectives for the treatment of retinal lactic acid metabolism disorders such as age-related macular degeneration and retinitis pigmentosa.

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1. Pan WW, Wubben TJ, Besirli CG. Photoreceptor metabolic reprogramming: current understanding and therapeutic implications[J/OL]. Commun Biol, 2021, 4(1): 245[2021-02-24]. https://pubmed.ncbi.nlm.nih.gov/33627778/. DOI: 10.1038/s42003-021-01765-3.
2. Huang J, Wang X, Li N, et al. YY1 lactylation aggravates autoimmune uveitis by enhancing microglial functions via inflammatory genes[J/OL]. Adv Sci (Weinh), 2024, 11(19): e2308031[2024-03-17]. https://pubmed.ncbi.nlm.nih.gov/38493498/. DOI: 10.1002/advs.202308031.
3. Hurley JB, Lindsay KJ, Du J. Glucose, lactate, and shuttling of metabolites in vertebrate retinas[J]. J Neurosci Res, 2015, 93(7): 1079-1092. DOI: 10.1002/jnr.23583.
4. Mori S, Kurimoto T, Miki A, et al. Aqp9 gene deletion enhances retinal ganglion cell (RGC) death and dysfunction induced by optic nerve crush: evidence that aquaporin 9 acts as an astrocyte-to-neuron lactate shuttle in concert with monocarboxylate transporters to support RGC function and survival[J]. Mol Neurobiol, 2020, 57(11): 4530-4548. DOI: 10.1007/s12035-020-02030-0.
5. Arai-Okuda M, Murai Y, Maeda H, et al. Potentially compromised systemic and local lactate metabolic balance in glaucoma, which could increase retinal glucose and glutamate concentrations[J/OL]. Sci Rep, 2024, 14(1): 3683[2024-02-14]. https://pubmed.ncbi.nlm.nih.gov/38355836/. DOI: 10.1038/s41598-024-54383-4.
6. Song J, Lee K, Park SW, et al. Lactic acid upregulates VEGF expression in macrophages and facilitates choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2018, 59(8): 3747-3754. DOI: 10.1167/iovs.18-23892.
7. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells?[J]. Trends Biochem Sci, 2016, 41(3): 211-218. DOI: 10.1016/j.tibs.2015.12.001.
8. Kanow MA, Giarmarco MM, Jankowski CS, et al. Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye[J/OL]. Elife, 2017, 6: e28899[2017-09-13]. https://pubmed.ncbi.nlm.nih.gov/28901286/. DOI: 10.7554/eLife.28899.
9. Lindsay KJ, Du J, Sloat SR, et al. Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina[J]. Proc Natl Acad Sci USA, 2014, 111(43): 15579-15584. DOI: 10.1073/pnas.1412441111.
10. Vohra R, Kolko M. Neuroprotection of the inner retina: Muller cells and lactate[J]. Neural Regen Res, 2018, 13(10): 1741-1742. DOI: 10.4103/1673-5374.238612.
11. Felmlee MA, Jones RS, Rodriguez-Cruz V, et al. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease[J]. Pharmacol Rev, 2020, 72(2): 466-485. DOI: 10.1124/pr.119.018762.
12. Han J, Kinoshita J, Bisetto S, et al. Role of monocarboxylate transporters in regulating metabolic homeostasis in the outer retina: Insight gained from cell-specific Bsg deletion[J]. FASEB J, 2020, 34(4): 5401-5419. DOI: 10.1096/fj.201902961R.
13. Akashi A, Miki A, Kanamori A, et al. Aquaporin 9 expression is required for l-lactate to maintain retinal neuronal survival[J]. Neurosci Lett, 2015, 589: 185-190. DOI: 10.1016/j.neulet.2015.01.063.
14. Philp NJ, Ochrietor JD, Rudoy C, et al. Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse[J]. Invest Ophthalmol Vis Sci, 2003, 44(3): 1305-1311. DOI: 10.1167/iovs.02-0552.
15. Muramatsu T. Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners[J]. J Biochem, 2016, 159(5): 481-490. DOI: 10.1093/jb/mvv127.
16. Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease[J/OL]. Signal Transduct Target Ther, 2022, 7(1): 305[2022-09-01]. https://pubmed.ncbi.nlm.nih.gov/36050306/. DOI: 10.1038/s41392-022-01151-3.
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18. Wang X, Fan W, Li N, et al. YY1 lactylation in microglia promotes angiogenesis through transcription activation-mediated upregulation of FGF2[J]. Genome Biol, 2023, 24(1): 87[2023-04-21]. https://pubmed.ncbi.nlm.nih.gov/37085894/. DOI: 10.1186/s13059-023-02931-y.
19. Campochiaro PA. Ocular neovascularization[J]. J Mol Med (Berl), 2013, 91(3): 311-321. DOI: 10.1007/s00109-013-0993-5.
20. Shinojima A, Lee D, Tsubota K, et al. Retinal diseases regulated by hypoxia-basic and clinical perspectives: a comprehensive review[J/OL]. J Clin Med, 2021, 10(23): 5496[2021-11-24]. https://pubmed.ncbi.nlm.nih.gov/34884197/. DOI: 10.3390/jcm10235496.
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22. Miller JW, Le Couter J, Strauss EC, et al. Vascular endothelial growth factor a in intraocular vascular disease[J]. Ophthalmology, 2013, 120(1): 106-114. DOI: 10.1016/j.ophtha.2012.07.038.
23. De Saedeleer CJ, Copetti T, Porporato PE, et al. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells[J]. PLoS One, 2012, 7(10): e46571[2012-10-17]. https://pubmed.ncbi.nlm.nih.gov/23082126/. DOI: 10.1371/journal.pone.0046571.
24. Yokosako K, Mimura T, Funatsu H, et al. Glycolysis in patients with age-related macular degeneration[J]. Open Ophthalmol J, 2014, 8: 39-47. DOI: 10.2174/1874364101408010039.
25. Barba I, Garcia-Ramirez M, Hernandez C, et al. Metabolic fingerprints of proliferative diabetic retinopathy: an 1H-NMR-based metabonomic approach using vitreous humor[J]. Invest Ophthalmol Vis Sci, 2010, 51(9): 4416-4421. DOI: 10.1167/iovs.10-5348.
26. Simsek IB, Artunay O. Evaluation of biochemical composition of vitreous of eyes of diabetic patients using proton magnetic resonance spectroscopy[J]. Curr Eye Res, 2017, 42(5): 754-758. DOI: 10.1080/02713683.2016.1242754.
27. Xu J, Zhang Y, Gan R, et al. Identification and validation of lactate metabolism-related genes in oxygen-induced retinopathy[J]. Sci Rep, 2023, 13(1): 13319[2023-08-16]. https://pubmed.ncbi.nlm.nih.gov/37587267/. DOI: 10.1038/s41598-023-40492-z.
28. Shen Z, Jiang L, Yuan Y, et al. Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury[J]. Cns Neurosci Ther, 2015, 21(3): 271-279. DOI: 10.1111/cns.12362.
29. Madaan A, Chaudhari P, Nadeau-Vallee M, et al. Müller cell-localized G-protein-coupled receptor 81 (hydroxycarboxylic acid receptor 1) regulates inner retinal vasculature via norrin/wnt pathways[J]. Am J Pathol, 2019, 189(9): 1878-1896. DOI: 10.1016/j.ajpath.2019.05.016.
30. Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation[J]. Nature, 2019, 574(7779): 575-580. DOI: 10.1038/s41586-019-1678-1.
31. Lauritzen KH, Morland C, Puchades M, et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism[J]. Cereb Cortex, 2014, 24(10): 2784-2795. DOI: 10.1093/cercor/bht136.
32. Morland C, Lauritzen KH, Puchades M, et al. The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain[J]. J Neurosci Res, 2015, 93(7): 1045-1055. DOI: 10.1002/jnr.23593.
33. Kolko M, Vosborg F, Henriksen UL, et al. Lactate transport and receptor actions in retina: potential roles in retinal function and disease[J]. Neurochem Res, 2016, 41(6): 1229-1236. DOI: 10.1007/s11064-015-1792-x.
34. Zhu D, Zhou J, Xu X. Influence of lactic acid on differential expression of vascular endothelial growth factor and pigment epithelium-derived factor in explants of rat retina[J]. Curr Eye Res, 2012, 37(11): 1025-1029. DOI: 10.3109/02713683.2012.695853.
35. Fan W, Wang X, Zeng S, et al. Global lactylome reveals lactylation-dependent mechanisms underlying Th17 differentiation in experimental autoimmune uveitis[J/OL]. Sci Adv, 2023, 9(42): 4655[2023-10-20]. https://pubmed.ncbi.nlm.nih.gov/37851814/. DOI: 10.1126/sciadv.adh4655.
36. Liu Z, Xu J, Ma Q, et al. Glycolysis links reciprocal activation of myeloid cells and endothelial cells in the retinal angiogenic niche[J/OL]. Sci Transl Med, 2020, 12(555): 1371[2020-08-05]. https://pubmed.ncbi.nlm.nih.gov/32759274/. DOI: 10.1126/scitranslmed.aay1371.
37. Zou Y, Jiang J, Li Y, et al. Quercetin regulates microglia M1/M2 polarization and alleviates retinal inflammation via ERK/STAT3 pathway[J/OL]. Inflammation, 2024: E1[2024-02-27]. https://pubmed.ncbi.nlm.nih.gov/38411775/. DOI: 10.1007/s10753-024-01997-5. [published online ahead of print].
38. Llorián-Salvador M, de la Fuente AG, McMurran CE, et al. Regulatory T cells limit age-associated retinal inflammation and neurodegeneration[J/OL]. Mol Neurodegener, 2024, 19(1): 32[2024-04-05]. https://pubmed.ncbi.nlm.nih.gov/38581053/. DOI: 10.1186/s13024-024-00724-w.
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