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 journalArticle

7 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 languageEnglish (US)
Pages (from-to)809-821.e6
JournalCell Metabolism
Volume31
Issue number4
DOIs
StatePublished - Apr 7 2020

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • 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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  • 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