Aerobic Glycolysis Hypothesis Through WNT/Beta-Catenin Pathway in Exudative Age-Related Macular Degeneration

Abstract

Exudative age-related macular degeneration (AMD) is characterized by molecular mechanisms responsible for the initiation of choroidal neovascularization (CNV). Inflammatory processes are associated with upregulation of the canonical WNT/beta-catenin pathway in exudative AMD. We focus this review on the link between WNT/beta-catenin pathway activation and neovascular progression in exudative AMD through activation of aerobic glycolysis for production of angiogenic factors. Increased WNT/beta-catenin pathway involves hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). WNT/beta-catenin pathway stimulates PI3K/Akt pathway and then HIF-1alpha which activates glycolytic enzymes: glucose transporter (Glut), pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDH-A), and monocarboxylate lactate transporter (MCT-1). This phenomenon is called aerobic glycolysis or the Warburg effect. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. Cytosolic pyruvate is converted into lactate through the action of LDH-A. In exudative AMD, high level of cytosolic lactate is correlated with increase of VEGF expression, the angiogenic factor of CNV. Photoreceptors in retina cells can metabolize glucose through aerobic glycolysis to protect them against oxidative damage, as cancer cells do.

The Proteomic Landscape in the Vitreous of Patients With Age-Related and Diabetic Retinal Disease

“…Increased levels of lactate dehydrogenase (LDHA; Table 2; Supplementary Table S2) could be a consequence of the Warburg effect as it has been reported for nAMD patients. 71 Increased conversion of pyruvate to lactate as it occurs during glycolysis is also suggested by data showing higher urinary lactate/pyruvate ratios in nAMD patients. 72 Low level complement activation is part of the immune tolerance in the immune privileged eye.…”

Activation de la glycolyse aérobie par la voie canonique WNT/β-caténine

“…De nombreuses études ont montré que la glycolyse aérobie est induite par la sur-activation de la voie de signalisation canonique WNT/caténine via une stimulation directe de la PDK1 et des transporteurs MCT-1 [37][38][39] (Figure 1). La -caténine stimule également la voie de signalisation PI3K/Akt (phosphatidylinositol 3 kinase/protéine kinase B) [40], une voie associée au métabolisme du glucose.…”

Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process

“…The Warburg effect is involved in various tumor and non-tumor diseases [ 168 ] and occurs during the process of fibroblast differentiation into myofibroblasts [ 169 ]. The Warburg effect is described as a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis despite the availability of oxygen [ 21 ].…”

“…Glycolysis is induced in a hypoxia-independent manner by (1) the WNT/β-catenin pathway activation via direct activation of WNT target genes, PDK1 and MCT-1, and via the stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) [ 168 , 174 , 175 , 176 ]; and (2) TGF-β1 pathway activation via HIF-1α stabilization [ 16 ].…”