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Fig. 1 | Molecular Brain

Fig. 1

From: Warburg effect hypothesis in autism Spectrum disorders

Fig. 1

Relation between activated WNT/β-catenin pathway and Warburg effect in ASD. Mutations in ASD lead to activate the presence of WNT ligands. Then, WNT binds both Frizzled and LRP 5/6 receptors to phosphorylate the AXIN/APC/GSK-3β complex. Thus, β-catenin phosphorylation is stopped and this inhibits its degradation into the proteasome. β-catenin accumulates in the cytosol and translocates to the nucleus to bind the complex TCF/LEF co transcription factors. WNT target gene transcription is activated by nuclear β-catenin (PDK, c-Myc, cyclin D1, MCT-1). Glucose also activates the WNT signaling. MCT-1 favors lactate expulsion out of the cell. WNT/β-catenin pathway activates tyrosine kinase receptors (TKRs) activity. Activated PI3K/Akt pathway stimulates glucose metabolism. Akt-transformed cells protect against reactive oxygen species stress (ROS) by inducing HIF-1α, which suppresses glucose entry into the TCA cycle. Stimulation of HIF-1α activity activates the expression of the glycolytic enzymes (GLUT, HK, PKM2, LDH-A). Aerobic glycolysis is observed with the increase of lactate production and the decrease of mitochondrial respiration. HIF-1α induced PDK phosphorylates PDH, which resulting in cytosolic pyruvate being shunted into lactate by inducing LDH-A activation. PDK inhibits the PDH complex into the mitochondria, thus pyruvate cannot be fully converted into acetyl-CoA and enter the TCA cycle. c-Myc and cyclin D1 also stimulates LDH-A activity which converts cytosolic pyruvate into lactate. Activated PKM2 translocates to the nucleus to bind β-catenin and then to induce the expression of c-Myc

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