Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration
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 betwe...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| author | Yara A. Samra Yusra Zaidi Pragya Rajpurohit Raju Raghavan Lun Cai Ismail Kaddour-Djebbar Amany Tawfik |
| author_facet | Yara A. Samra Yusra Zaidi Pragya Rajpurohit Raju Raghavan Lun Cai Ismail Kaddour-Djebbar Amany Tawfik |
| author_sort | Yara A. Samra |
| collection | DOAJ |
| description | 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 “Warburg”, 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 β-synthase) <i>cbs<sup>+/−</sup></i> and <i>cbs<sup>−/−</sup></i> 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 <i>cbs<sup>+/+</sup></i>, <i>cbs<sup>+/−</sup></i>, and <i>cbs<sup>−/−</sup></i> 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. |
| first_indexed | 2024-03-09T12:26:13Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:26:13Z |
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| spelling | doaj.art-dfd48e7f15b04bfe9b1d90a789afb1a52023-11-30T22:34:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242107110.3390/ijms24021071Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular DegenerationYara A. Samra0Yusra Zaidi1Pragya Rajpurohit2Raju Raghavan3Lun Cai4Ismail Kaddour-Djebbar5Amany Tawfik6Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, EgyptDepartment of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Pharmacology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Pharmacology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USADepartment of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USAAge-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 “Warburg”, 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 β-synthase) <i>cbs<sup>+/−</sup></i> and <i>cbs<sup>−/−</sup></i> 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 <i>cbs<sup>+/+</sup></i>, <i>cbs<sup>+/−</sup></i>, and <i>cbs<sup>−/−</sup></i> 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.https://www.mdpi.com/1422-0067/24/2/1071N-methyl-D-aspartate receptorhomocysteineage-related macular degenerationblood retinal barriercystathionine-β—synthasemouse |
| spellingShingle | Yara A. Samra Yusra Zaidi Pragya Rajpurohit Raju Raghavan Lun Cai Ismail Kaddour-Djebbar Amany Tawfik Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration International Journal of Molecular Sciences N-methyl-D-aspartate receptor homocysteine age-related macular degeneration blood retinal barrier cystathionine-β—synthase mouse |
| title | Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration |
| title_full | Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration |
| title_fullStr | Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration |
| title_full_unstemmed | Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration |
| title_short | Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration |
| title_sort | warburg effect as a novel mechanism for homocysteine induced features of age related macular degeneration |
| topic | N-methyl-D-aspartate receptor homocysteine age-related macular degeneration blood retinal barrier cystathionine-β—synthase mouse |
| url | https://www.mdpi.com/1422-0067/24/2/1071 |
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