Glutamine Metabolism Is Required for Collagen Protein Synthesis in Lung Fibroblasts
| Autor: | Leah J. Witt, Robert B. Hamanaka, Angelo Y. Meliton, Gökhan M. Mutlu, E.M. O'Leary, G. Gokalp, Yufeng Tian, Nickolai O. Dulin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine chemistry.chemical_classification Glutaminolysis Chemistry Glutaminase Glutamate dehydrogenase Clinical Biochemistry Cell Biology Glutamine 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure 030228 respiratory system Biochemistry medicine Proline Fibroblast Oxoglutarate dehydrogenase complex Molecular Biology Amino acid synthesis |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 61:597-606 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2019-0008oc |
| Popis: | Idiopathic pulmonary fibrosis (IPF) is characterized by the transforming growth factor (TGF)-β-dependent differentiation of lung fibroblasts into myofibroblasts, leading to excessive deposition of extracellular matrix proteins, which distort lung architecture and function. Metabolic reprogramming in myofibroblasts is emerging as an important mechanism in the pathogenesis of IPF, and recent evidence suggests that glutamine metabolism is required in myofibroblasts, although the exact role of glutamine in myofibroblasts is unclear. In the present study, we demonstrate that glutamine and its conversion to glutamate by glutaminase are required for TGF-β-induced collagen protein production in lung fibroblasts. We found that metabolism of glutamate to α-ketoglutarate by glutamate dehydrogenase or the glutamate-pyruvate or glutamate-oxaloacetate transaminases is not required for collagen protein production. Instead, we discovered that the glutamate-consuming enzymes phosphoserine aminotransferase 1 (PSAT1) and aldehyde dehydrogenase 18A1 (ALDH18A1)/Δ1-pyrroline-5-carboxylate synthetase (P5CS) are required for collagen protein production by lung fibroblasts. PSAT1 is required for de novo glycine production, whereas ALDH18A1/P5CS is required for de novo proline production. Consistent with this, we found that TGF-β treatment increased cellular concentrations of glycine and proline in lung fibroblasts. Our results suggest that glutamine metabolism is required to promote amino acid biosynthesis and not to provide intermediates such as α-ketoglutarate for oxidation in mitochondria. In support of this, we found that inhibition of glutaminolysis has no effect on cellular oxygen consumption and that knockdown of oxoglutarate dehydrogenase has no effect on the ability of fibroblasts to produce collagen protein. Our results suggest that amino acid biosynthesis pathways may represent novel therapeutic targets for treatment of fibrotic diseases, including IPF. |
| Databáze: | OpenAIRE |
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