Serine Catabolism Feeds NADH when Respiration Is Impaired

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

doi:10.1016/j.cmet.2020.02.017

Serine Catabolism Feeds NADH when Respiration Is Impaired

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

Research output: Contribution to journal › Article › peer-review

85 Scopus citations

Abstract

NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4−/−), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.

Original language	English (US)
Pages (from-to)	809-821.e6
Journal	Cell Metabolism
Volume	31
Issue number	4
DOIs	https://doi.org/10.1016/j.cmet.2020.02.017
State	Published - Apr 7 2020

All Science Journal Classification (ASJC) codes

Molecular Biology
Physiology
Cell Biology

Keywords

MTHFD2
NAD
NADH
SHMT2
complex I inhibitor
hypoxia
methylene tetrahydrofolate dehydrogenase
mitochondrial disease
redox
respiration inhibition
serine catabolism
serine hydroxymethyltransferase

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10.1016/j.cmet.2020.02.017

Cite this

Yang, L., Garcia Canaveras, J. C., Chen, Z., Wang, L., Liang, L., Jang, C., Mayr, J. A., Zhang, Z., Ghergurovich, J. M., Zhan, L., Joshi, S., Hu, Z., McReynolds, M. R., Su, X., White, E., Morscher, R. J., & Rabinowitz, J. D. (2020). Serine Catabolism Feeds NADH when Respiration Is Impaired. Cell Metabolism, 31(4), 809-821.e6. https://doi.org/10.1016/j.cmet.2020.02.017

@article{bbe341234708415e94ab5c3e8468276a,

title = "Serine Catabolism Feeds NADH when Respiration Is Impaired",

abstract = "NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4−/−), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.",

keywords = "MTHFD2, NAD, NADH, SHMT2, complex I inhibitor, hypoxia, methylene tetrahydrofolate dehydrogenase, mitochondrial disease, redox, respiration inhibition, serine catabolism, serine hydroxymethyltransferase",

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

note = "Funding Information: We thank Reuben Shaw (Salk Institute), Greg Ducker (The University of Utah), Serina Ng (TGen), Haiyong Han (TGen), and Michel Nofal and all other members of the Rabinowitz laboratory. This work was supported by funding to J.D.R. from the US National Institutes of Health (NIH) ( R01CA163591 and DP1DK113643 ) and Stand Up to Cancer ( SU2CAACR-DT-20-16 ). S.J., Z.H., and L.Z. were supported by NIH grants to E.W. ( R01CA163591 and R01 CA130893 ). L.Y. was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research . J.C.G.C. is supported by funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 751423. C.J. is supported by fellowship from American Diabetes Association . M.R.M is supported by both the Hanna H. Gray Fellows Program of the Howard Hughes Medical Institute and the Burroughs Wellcome Fund Postdoctoral Enrichment Program. Funding Information: We thank Reuben Shaw (Salk Institute), Greg Ducker (The University of Utah), Serina Ng (TGen), Haiyong Han (TGen), and Michel Nofal and all other members of the Rabinowitz laboratory. This work was supported by funding to J.D.R. from the US National Institutes of Health (NIH) (R01CA163591 and DP1DK113643) and Stand Up to Cancer (SU2CAACR-DT-20-16). S.J. Z.H. and L.Z. were supported by NIH grants to E.W. (R01CA163591 and R01 CA130893). L.Y. was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research. J.C.G.C. is supported by funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 751423. C.J. is supported by fellowship from American Diabetes Association. M.R.M is supported by both the Hanna H. Gray Fellows Program of the Howard Hughes Medical Institute and the Burroughs Wellcome Fund Postdoctoral Enrichment Program. L.Y. and J.D.R. conceived the project and designed the experiments. L.Y. R.J.M. and J.D.R. wrote the manuscript. L.Y. J.C.G.C. Z.C. L.L. and C.J. performed biochemical experiments. L.Y. X.S. and L.W. performed LC-MS data analysis. Z.Z. J.M.G. L.Z. S.J. M.R.M. and E.W. were involved in study design and data interpretation. L.Y. S.J. Z.H. and L.Z. performed the in vivo isotope tracing experiments. R.J.M. and J.A.M. contributed primary patient cell lines. All authors reviewed and edited the manuscript before submission. Joshua Rabinowitz is a member of the Rutgers Cancer Institute of New Jersey and the University of Pennsylvania Diabetes Research Center; a consultant or advisor to Pfizer, Agios Pharmaceuticals, Kadmon Pharmaceuticals, L.E.A.F. Pharmaceuticals, and Rafael Pharmaceuticals; and co-founder of Raze Therapeutics. Eileen White is an SAB member, founder of Vescor Therapeutics, and SAB member of Forma Therapeutics. Princeton University has filed patents related to SHMT inhibitors and their uses. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = apr,

day = "7",

doi = "10.1016/j.cmet.2020.02.017",

language = "English (US)",

volume = "31",

pages = "809--821.e6",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "4",

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TY - JOUR

T1 - Serine Catabolism Feeds NADH when Respiration Is Impaired

AU - Yang, Lifeng

AU - Garcia Canaveras, Juan Carlos

AU - Chen, Zihong

AU - Wang, Lin

AU - Liang, Lingfan

AU - Jang, Cholsoon

AU - Mayr, Johannes A.

AU - Zhang, Zhaoyue

AU - Ghergurovich, Jonathan M.

AU - Zhan, Le

AU - Joshi, Shilpy

AU - Hu, Zhixian

AU - McReynolds, Melanie R.

AU - Su, Xiaoyang

AU - White, Eileen

AU - Morscher, Raphael J.

AU - Rabinowitz, Joshua D.

N1 - Funding Information: We thank Reuben Shaw (Salk Institute), Greg Ducker (The University of Utah), Serina Ng (TGen), Haiyong Han (TGen), and Michel Nofal and all other members of the Rabinowitz laboratory. This work was supported by funding to J.D.R. from the US National Institutes of Health (NIH) ( R01CA163591 and DP1DK113643 ) and Stand Up to Cancer ( SU2CAACR-DT-20-16 ). S.J., Z.H., and L.Z. were supported by NIH grants to E.W. ( R01CA163591 and R01 CA130893 ). L.Y. was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research . J.C.G.C. is supported by funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 751423. C.J. is supported by fellowship from American Diabetes Association . M.R.M is supported by both the Hanna H. Gray Fellows Program of the Howard Hughes Medical Institute and the Burroughs Wellcome Fund Postdoctoral Enrichment Program. Funding Information: We thank Reuben Shaw (Salk Institute), Greg Ducker (The University of Utah), Serina Ng (TGen), Haiyong Han (TGen), and Michel Nofal and all other members of the Rabinowitz laboratory. This work was supported by funding to J.D.R. from the US National Institutes of Health (NIH) (R01CA163591 and DP1DK113643) and Stand Up to Cancer (SU2CAACR-DT-20-16). S.J. Z.H. and L.Z. were supported by NIH grants to E.W. (R01CA163591 and R01 CA130893). L.Y. was supported by a postdoctoral fellowship from the New Jersey Commission on Cancer Research. J.C.G.C. is supported by funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 751423. C.J. is supported by fellowship from American Diabetes Association. M.R.M is supported by both the Hanna H. Gray Fellows Program of the Howard Hughes Medical Institute and the Burroughs Wellcome Fund Postdoctoral Enrichment Program. L.Y. and J.D.R. conceived the project and designed the experiments. L.Y. R.J.M. and J.D.R. wrote the manuscript. L.Y. J.C.G.C. Z.C. L.L. and C.J. performed biochemical experiments. L.Y. X.S. and L.W. performed LC-MS data analysis. Z.Z. J.M.G. L.Z. S.J. M.R.M. and E.W. were involved in study design and data interpretation. L.Y. S.J. Z.H. and L.Z. performed the in vivo isotope tracing experiments. R.J.M. and J.A.M. contributed primary patient cell lines. All authors reviewed and edited the manuscript before submission. Joshua Rabinowitz is a member of the Rutgers Cancer Institute of New Jersey and the University of Pennsylvania Diabetes Research Center; a consultant or advisor to Pfizer, Agios Pharmaceuticals, Kadmon Pharmaceuticals, L.E.A.F. Pharmaceuticals, and Rafael Pharmaceuticals; and co-founder of Raze Therapeutics. Eileen White is an SAB member, founder of Vescor Therapeutics, and SAB member of Forma Therapeutics. Princeton University has filed patents related to SHMT inhibitors and their uses. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/4/7

Y1 - 2020/4/7

N2 - NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4−/−), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.

AB - NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4−/−), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.

KW - MTHFD2

KW - NAD

KW - NADH

KW - SHMT2

KW - complex I inhibitor

KW - hypoxia

KW - methylene tetrahydrofolate dehydrogenase

KW - mitochondrial disease

KW - redox

KW - respiration inhibition

KW - serine catabolism

KW - serine hydroxymethyltransferase

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M3 - Article

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SN - 1550-4131

VL - 31

SP - 809-821.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

Serine Catabolism Feeds NADH when Respiration Is Impaired

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