Serine Catabolism Feeds NADH when Respiration Is Impaired

Yang, Lifeng; Canaveras, Juan Carlos Garcia; Chen, Zihong; Wang, Lin; Liang, Lingfan; Jang, Cholsoon; Mayr, Johannes A.; Zhang, Zhaoyue; Ghergurovich, Jonathan M.; Zhan, Lin; Joshi, Shilpy; Hu, Zhixian; McReynolds, Melanie R.; Su, Xiaoyang; White, Eileen; Morscher, Raphael J.; Rabinowitz, Joshua D.

doi:10.1016/j.cmet.2020.02.017

Cited by 151 publications

(147 citation statements)

References 75 publications

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“…To examine whether these observations hold in vivo, we infused [U- 13 C]methionine via jugular venous catheter into C57BL/6J mice bearing subcutaneous pancreatic ductal adenocarcinoma (PDAC) allograft tumors [38], achieving an enrichment of 30-60% in serum, tumors and most tissues ( Figure 1D). This extent of labeling is adequate for robust label detection while avoiding severe metabolic perturbation by the labeled methionine infusion.…”

Section: Methionine Comes Mainly From Uptake Rather Than Homocysteinementioning

confidence: 99%

“…Animal studies were approved and conducted under the supervision of the Princeton University Institutional Animal Care and Use Committee. PDAC tumor tissues derived from LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; and Pdx-1-Cre (KPC) mice were used to generate a syngeneic xenograft model, as previously described [38]. Briefly, tumor tissues were minced, mixed with Matrigel (Corning Cat #354234 in 1:1 ratio (v/v)) and injected (200 µL) into the subcutaneous left flank of C57BL/6J mice (Charles River).…”

Section: Mouse Infusion Studiesmentioning

confidence: 99%

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Methionine synthase supports tumor tetrahydrofolate pools

Wang

Ghergurovich

Yang

et al. 2020

Preprint

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Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyltetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that methionine synthase is only a minor source of methionine in cell culture, tissues, or xenografted tumors. Instead, methionine synthase is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumor cells leads to folate trapping, purine synthesis stalling, nucleotide depletion, and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating THF for use in one-carbon metabolism.

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Section: Methionine Comes Mainly From Uptake Rather Than Homocysteinementioning

confidence: 99%

Section: Mouse Infusion Studiesmentioning

confidence: 99%

Methionine synthase supports tumor tetrahydrofolate pools

Wang

Ghergurovich

Yang

et al. 2020

Preprint

Self Cite

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“…In a recent study, levels of NADH have been tied to one-carbon metabolism and cellular respiration (Yang, Garcia Canaveras et al, 2020). The TCA cycle as well as the one-carbon metabolism produce NADH in mitochondria; however, only the TCA cycle is regulated by substrate inhibition through NADH.…”

Section: Discussionmentioning

confidence: 99%

A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway

Straub

Weraarpachai

Shoubridge

2020

Preprint

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Mutations in CHCHD10, coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis (ALS). Mutation-specific toxic gain of function or haploinsuffuciency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant we integrated transcriptomic, metabolomic and proteomic data sets in patient cells subjected to nutrient stress. Patient cells had a complex I deficiency resulting in an increased NADH/NAD + ratio, downregulation of the TCA cycle, and a reorganization of one carbon metabolism. This led to phosphorylation of AMPK, activation of an endoplasmic reticulum and mitochondrial unfolded protein response (UPR), and the production of GDF15 and FGF21, which are markers of mitochondrial disease. The endoplasmic reticulum UPR was mediated through the IRE1/XBP1 pathway, and was accompanied by reduced eIF2alpha phosphorylation, dephosphorylation of both JNK isoforms, and up regulation of several dual specific phosphatases. This study demonstrates that loss of CHCHD10 function elicits a striking energy deficit that activates cellular stress pathways, which may underlie the selective vulnerability of motor neurons.

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“…Recent studies have shown that mitochondrial FOCM enzymes are particularly strongly upregulated in proliferating lymphocytes and human cancers ( 17 , 69 – 71 ), which, in part, reflects the role of mitochondrial FOCM in supporting critical cellular functions such as cell proliferation and mitochondrial respiration. Some mitochondrial compartment–specific uses of mitochondrial folate one-carbon units include the local biosynthesis of dTTP ( 20 ) and of N -formylmethionine (fMet) ( 72 ), tRNA modification ( 73 ), oxidative phosphorylation (OXPHOS) complex assembly ( 74 ) and redox state regulation ( 75 , 76 ).…”

Section: Intracellular Compartmentalization Of One-carbon Metabolismmentioning

confidence: 99%

“…Serine catabolism by the mitochondrial folate pathway was also identified as the major source of NAD(H) for cells with impaired electron transport chain activity ( 76 ). In the mitochondria, SHMT2 converts serine to glycine while producing 5,10-methylene-THF.…”

Section: Intracellular Compartmentalization Of One-carbon Metabolismmentioning

confidence: 99%

The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function

Xiu

Field

2020

Current Developments in Nutrition

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Folate-mediated one-carbon metabolism (FOCM) is compartmentalized within human cells to the cytosol, nucleus, and mitochondria. The recent identifications of mitochondria-specific, folate-dependent thymidylate (dTMP) synthesis together with discoveries indicating the critical role of mitochondrial FOCM in cancer progression has renewed interest in understanding this metabolic pathway. The goal of this narrative review is to summarize recent advances in the field of one-carbon metabolism, with an emphasis on the biological importance of mitochondrial FOCM in maintaining mitochondrial DNA (mtDNA) integrity and mitochondrial function, as well as the reprogramming of mitochondrial FOCM in cancer. Elucidation of the roles and regulation of mitochondrial FOCM will contribute to a better understanding of the mechanisms underlying folate-associated pathologies.

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Serine Catabolism Feeds NADH when Respiration Is Impaired

Cited by 151 publications

References 75 publications

Methionine synthase supports tumor tetrahydrofolate pools

Methionine synthase supports tumor tetrahydrofolate pools

A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway

The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function

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