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Am J Respir Cell Mol Biol. 2018 Mar;58(3):378-390. doi: 10.1165/rcmb.2017-0238OC.

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

Author information

1
1 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
2
2 Department of Geriatrics and Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and.
3
3 Department of Pulmonary, Allergy, and Critical Care Medicine, The Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
4
4 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.

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.

KEYWORDS:

collagen; fibrosis; glutaminolysis; mTORC1; α-ketoglutarate

PMID:
29019707
PMCID:
PMC5854958
[Available on 2019-03-01]
DOI:
10.1165/rcmb.2017-0238OC
[Indexed for MEDLINE]

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