Figure 4.

Metabolic reprogramming of activated lung fibroblasts. Activated lung fibroblasts utilize aerobic glycolysis (Warburg effect) over mitochondrial glucose oxidation. Although this metabolic reprogramming event generates less ATP than mitochondrial respiration, it also supplies various biosynthetic intermediates for activated myofibroblasts. This includes the production of glucose-6-P, which is diverted to the pentose phosphate pathway for the production of NADPH and ribose-5-P, and the production of glycerate-3-P, which is diverted to the de novo serine and glycine synthesis pathway. Aerobic glycolysis also yields large amounts of lactate acid, which serves to activate latent TGF-β1 by reducing extracellular pH. By-products of aerobic glycolysis can also feed the TCA cycle, leading to an increase in succinate production. Succinate stabilizes HIF-1α, which then amplifies glycolysis by inducing the expression of various glycolytic genes and promotes myofibroblast differentiation via the induction of α-SMA expression. Activated myofibroblasts also exhibit enhanced glutaminase activity, leading to augmented glutaminolysis, which in turn promotes the conversion of glutamine to glutamate. Glutamine metabolism via the TCA cycle can yield high levels of α-KG, which activates mTOR, leading to increased transcription, translation, and hydroxylation of collagen. Abbreviations: α-KG, alpha-ketoglutarate; α-SMA, alpha-smooth muscle actin; GLUT1, glucose transporter 1; HIF-1α, hypoxia-induced factor-1 alpha; LDH, lactate dehydrogenase; mTOR, mammalian target of rapamycin; P, phosphate; PHGDH, phosphoglycerate dehydrogenase; PPP, pentose phosphate pathway; TCA, tricarboxylic acid; TGF-β1, transforming growth factor-beta 1.