Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress
| Autor: | Jiajun Zhu, Sara Violante, Craig B. Thompson, Ronald C. Hendrickson, Mirela Berisa, Justin R. Cross, Weige Qin, Simon Schwörer |
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| Rok vydání: | 2020 |
| Předmět: |
Proline
Glutamine Citric Acid Cycle Oxidative phosphorylation Oxidative Phosphorylation General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biosynthesis Transforming Growth Factor beta Animals Humans Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Reactive oxygen species General Immunology and Microbiology ATP synthase biology General Neuroscience Articles Metabolism Fibrosis Mitochondria Cell biology Citric acid cycle Glucose chemistry NIH 3T3 Cells biology.protein Collagen Energy Metabolism Reactive Oxygen Species Oxidation-Reduction 030217 neurology & neurosurgery |
| Zdroj: | EMBO J |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.2019103334 |
| Popis: | The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor-beta (TGFβ) play a critical role in wound healing. How TGFβ supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGFβ promotes protein translation at least in part by increasing the mitochondrial oxidation of glucose and glutamine carbons to support the bioenergetic demand of translation. Surprisingly, we found that in addition to stimulating the entry of glucose and glutamine carbon into the TCA cycle, TGFβ induced the biosynthesis of proline from glutamine in a Smad4-dependent fashion. Metabolic manipulations that increased mitochondrial redox generation promoted proline biosynthesis, while reducing mitochondrial redox potential and/or ATP synthesis impaired proline biosynthesis. Thus, proline biosynthesis acts as a redox vent, preventing the TGFβ-induced increase in mitochondrial glucose and glutamine catabolism from generating damaging reactive oxygen species (ROS) when TCA cycle activity exceeds the ability of oxidative phosphorylation to convert mitochondrial redox potential into ATP. In turn, the enhanced synthesis of proline supports TGFβ-induced production of matrix proteins. |
| Databáze: | OpenAIRE |
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