Glutamine Metabolism Is Required for Collagen Protein Synthesis in Lung Fibroblasts

Hamanaka, Robert B.; O’Leary, Erin; Witt, Leah J.; Tian, Yufeng; Gökalp, G.; Meliton, Angelo Y.; Dulin, Nickolai O.; Mutlu, Gökhan M.

doi:10.1165/rcmb.2019-0008oc

Cited by 114 publications

(98 citation statements)

References 31 publications

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“…While glutamine carbon did not contribute to serine and glycine (Fig EV2H), both serine and glycine were substantially labeled by the glutamine alpha‐nitrogen (Fig EV2I). TGFβ treatment further increased alpha‐nitrogen labeling of serine and glycine (Fig EV2I), consistent with TGFβ‐induced expression of PSAT1 (Hamanaka et al , ) which catalyzes the transamination reaction in the serine biosynthetic pathway.…”

Section: Resultssupporting

confidence: 77%

“…For instance, TGFβ‐mediated activation and differentiation of fibroblasts into extracellular matrix (ECM)‐producing myofibroblasts are accompanied by an increase in glucose uptake, glycolytic metabolism, and activation of the serine/glycine biosynthetic pathway (Andrianifahanana et al , ; Nigdelioglu et al , ; Selvarajah et al , ). In addition, glutaminolysis is required for TGFβ‐induced collagen production (Bernard et al , ; Hamanaka et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress

et al. 2020

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The production and secretion of matrix proteins upon stimulation of fibroblasts by transforming growth factor-beta (TGFb) play a critical role in wound healing. How TGFb supports the bioenergetic cost of matrix protein synthesis is not fully understood. Here, we show that TGFb 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, TGFb 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 TGFb-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 TGFb-induced production of matrix proteins.

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Section: Resultssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress

et al. 2020

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“…Thus, it can be concluded that fibroblasts prefer exogenous Gln, as an intermediate of proline for effective collagen biosynthesis. The data are supported by recent studies showing that glutamine is indispensable for conversion into Pro (but not into α-ketoglutarate) to support collagen protein biosynthesis [55]. Moreover, it was found that intracellular concentration of Pro was drastically decreased after Gln withdrawal [30].…”

Section: Role Of Proline and Glutamine In Regulation Of Collagen Biossupporting

confidence: 79%

Proline-dependent regulation of collagen metabolism

Karna

Szoka

Huynh

et al. 2019

Cell. Mol. Life Sci.

119

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This review is focused on recent data on the role of proline (Pro) in collagen biosynthesis and cellular metabolism. It seems obvious that one of the main substrates for collagen biosynthesis Pro is required to form collagen molecule. The question raised in this review is whether the Pro for collagen biosynthesis is synthesized "de novo", comes directly from degraded proteins or it is converted from other amino acids. Recent data provided evidence that extracellular Pro (added to culture medium) had significant, but relatively little impact on collagen biosynthesis in fibroblasts (the main collagen synthesized cells) cultured in the presence of glutamine (Gln). However, extracellular Pro drastically increased collagen biosynthesis in the cells cultured in Gln-free medium. It suggests that Pro availability determines the rate of collagen biosynthesis and demand for Pro in fibroblasts is predominantly met by conversion from Gln. The potential mechanism of this process as well as possible implication of this knowledge in pharmacotherapy of connective tissue diseases is discussed in this review.

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“…The Seahorse XF e 24 Extracellular Flux Analyzer (Seahorse Bioscience, North Billerica, MA), was used to measure oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) as we have previously described (Nigdelioglu, Hamanaka et al 2016, Hamanaka, O'Leary et al 2019, Soberanes, Misharin et al 2019, Woods, Kimmig et al 2020).…”

Section: Seahorse Analysismentioning

confidence: 99%

Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

Sun

Meliton

et al. 2020

eLife

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Particulate matter (PM) air pollution causes cardiopulmonary mortality via macrophage-driven lung inflammation; however, the mechanisms are incompletely understood. RNA-sequencing demonstrated Acod1 (Aconitate decarboxylase 1) as one of the top genes induced by PM in macrophages. Acod1 encodes a mitochondrial enzyme that produces itaconate, which has been shown to exert anti-inflammatory effects via NRF2 after LPS. Here, we demonstrate that PM induces Acod1 and itaconate, which reduced mitochondrial respiration via complex II inhibition. Using Acod1-/- mice, we found that Acod1/endogenous itaconate does not affect PM-induced inflammation or NRF2 activation in macrophages in vitro or in vivo. In contrast, exogenous cell permeable itaconate, 4-octyl itaconate (OI) attenuated PM-induced inflammation in macrophages. OI was sufficient to activate NRF2 in macrophages; however, NRF2 was not required for the anti-inflammatory effects of OI. We conclude that the effects of itaconate production on inflammation are stimulus-dependent, and that there are important differences between endogenous and exogenously-applied itaconate.

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Glutamine Metabolism Is Required for Collagen Protein Synthesis in Lung Fibroblasts

Cited by 114 publications

References 31 publications

Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress

Proline biosynthesis is a vent for TGFβ‐induced mitochondrial redox stress

Proline-dependent regulation of collagen metabolism

Endogenous itaconate is not required for particulate matter-induced NRF2 expression or inflammatory response

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