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Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress
Author(s) -
Schwörer Simon,
Berisa Mirela,
Violante Sara,
Qin Weige,
Zhu Jiajun,
Hendrickson Ronald C,
Cross Justin R,
Thompson Craig B
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103334
Subject(s) - biology , biosynthesis , proline , redox , biochemistry , mitochondrion , oxidative stress , microbiology and biotechnology , amino acid , gene , materials science , metallurgy
The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor‐beta ( TGF β) play a critical role in wound healing. How TGF β supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGF β 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, TGF β 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 TGF β‐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 TGF β‐induced production of matrix proteins.