{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:53:10Z","timestamp":1790635990302,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01 EY029751-01\u2013NEI00072"],"award-info":[{"award-number":["R01 EY029751-01\u2013NEI00072"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Age-related macular degeneration (AMD) is a major cause of blindness. Recent studies have reported impaired glycolysis in AMD patients with a high lactate\/pyruvate ratio. Elevated homocysteine (Hcy) (Hyperhomocysteinemia, HHcy) was observed in several clinical studies, reporting an association between HHcy and AMD. We established the effect of HHcy on barrier function, retinal pigment epithelium (RPE) structure, and induced choroidal neovascularization (CNV) in mice. We hypothesize that HHcy contributes to AMD by inducing a metabolic switch in the mitochondria, in which cells predominantly produce energy by the high rate of glycolysis, or \u201cWarburg\u201d, effect. Increased glycolysis results in an increased production of lactate, cellular acidity, activation of angiogenesis, RPE barrier dysfunction, and CNV. Evaluation of cellular energy production under HHcy was assessed by seahorse analysis, immunofluorescence, and western blot experiments. The seahorse analysis evaluated the extracellular acidification rate (ECAR) as indicative of glycolysis. HHcy showed a significant increase in ECAR both in vivo using (Cystathionine \u03b2-synthase) cbs+\/\u2212 and cbs\u2212\/\u2212 mice retinas and in vitro (Hcy-treated ARPE-19) compared to wild-type mice and RPE cells. Moreover, HHcy up-regulated glycolytic enzyme (Glucose transporter-1 (GlUT-1), lactate dehydrogenase (LDH), and hexokinase 1 (HK1)) in Hcy-treated ARPE-19 and primary RPE cells isolated from cbs+\/+, cbs+\/\u2212, and cbs\u2212\/\u2212 mice retinas. Inhibition of GLUT-1 or blocking of N-methyl-D-aspartate receptors (NMDAR) reduced glycolysis in Hcy-treated RPE and improved albumin leakage and CNV induction in Hcy-injected mice eyes. The current study suggests that HHcy causes a metabolic switch in the RPE cells from mitochondrial respiration to glycolysis during AMD and confirms the involvement of NMDAR in this process. Therefore, targeting Glycolysis or NMDAR could be a novel therapeutic target for AMD.<\/jats:p>","DOI":"10.3390\/ijms24021071","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:48:19Z","timestamp":1672969699000},"page":"1071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"24","author":[{"given":"Yara A.","family":"Samra","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-0398","authenticated-orcid":false,"given":"Yusra","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragya","family":"Rajpurohit","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju","family":"Raghavan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lun","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail","family":"Kaddour-Djebbar","sequence":"additional","affiliation":[{"name":"Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0245-8256","authenticated-orcid":false,"given":"Amany","family":"Tawfik","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Eye Research Institute, Oakland University, Rochester, MI 48309-4479, USA"},{"name":"Eye Research Center (OUWB)\/ERC, William Beaumont School of Medicine, Royal Oak, MI 48309-4479, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.2174\/157015908784533851","article-title":"Neurodegenerative diseases of the retina and potential for protection and recovery","volume":"6","author":"Schmidt","year":"2008","journal-title":"Curr. 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