Glutaminolysis Promotes Collagen Translation and Stability via α-Ketoglutarate–mediated mTOR Activation and Proline Hydroxylation

Abstract

Glutaminolysis is the metabolic process of glutamine, aberration of which has been implicated in several pathogeneses. Although we and others recently found a diversity of metabolic dysregulation in organ fibrosis, it is unknown if glutaminolysis regulates the profibrotic activities of myofibroblasts, the primary effector in this pathology. In this study, we found that lung myofibroblasts demonstrated significantly augmented glutaminolysis that was mediated by elevated glutaminase 1 (Gls1). Inhibition of glutaminolysis by specific Gls1 inhibitors CB-839 and BPTES as well as Gls1 siRNA blunted the expression of collagens but not that of fibronectin, elastin, or myofibroblastic marker smooth muscle actin-α. We found that glutaminolysis enhanced collagen translation and stability, which were mediated by glutaminolysis-dependent mTOR complex 1 activation and collagen proline hydroxylation, respectively. Furthermore, we found that the amount of the glutaminolytic end product α-ketoglutarate (α-KG) was increased in myofibroblasts. Similar to glutaminolysis, α-KG activated mTOR complex 1 and promoted the expression of collagens but not of fibronectin, elastin, or smooth muscle actin-α. α-KG also remarkably inhibited collagen degradation in fibroblasts. Taken together, our studies identified a previously unrecognized mechanism by which a major metabolic program regulates the exuberant production of collagens in myofibroblasts and suggest that glutaminolysis is a novel therapeutic target for treating organ fibrosis, including idiopathic pulmonary fibrosis.

mTORC1 amplifies the ATF4-dependent de novo serine-glycine pathway to supply glycine during TGF-β 1 –induced collagen biosynthesis

“…These studies report that the expression of the TGF-β 1 -induced matrix glycoprotein, fibronectin, was also not dependent on mitochondrial biogenesis. We further provide herein evidence that mTOR inhibition does not interfere with TGF-β 1 -induced myofibroblast differentiation which is also in agreement with a previous report(58). Taken together, a picture now seems to be emerging that TGF-β 1 –induced fibroblast differentiation and matrix synthesis, the two cardinal features that define the myofibroblast phenotype, may have distinct metabolic requirements that could be targeted separately or in combination to slowdown both the restrictive physiologic impairment and the gas exchange impairment that characterize the fibrotic lung in IPF.…”

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

“…Apart from N-glycosylation and O-GlcNacylation, UDP-GlcNAc is also a substrate for HA synthesis. HA is a key component of the ECM, and therefore, inhibition of HBP is likely to affect the ECM in a tumor (15,(56)(57)(58). Thus, inhibition of GFAT1 effectively inhibits metabolic flux through this pathway and is likely to affect the glycosylation profile of the tumor cells as well as the components of the ECM.…”

Plasma Metabolomic Profiles Differentiate Patients With Dilated Cardiomyopathy and Ischemic Cardiomyopathy

“…These findings further highlight the COX pathway as vital treatment targets in ICM patients. In addition, the impaired energy utilization in ICM resulted in increased glutaminolysis, which can produce α-ketoglutarate to replenish the Krebs cycle, serving as an anaplerotic source of carbon for the formation of non-essential amino acids and lipids ( 44 , 45 ). In addition, glutamate is used for the synthesis of the antioxidant glutathione, which promotes redox and limiting oxidative stress through maintenance of cardiac glutathione metabolism ( 46 ).…”