Serine Catabolism Feeds NADH when Respiration Is Impaired.
- Yang L Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Garcia Canaveras JC Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Chen Z Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Wang L Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Liang L School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
- Jang C Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Mayr JA Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg 5020, Austria.
- Zhang Z Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Ghergurovich JM Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
- Zhan L Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
- Joshi S Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
- Hu Z Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
- McReynolds MR Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
- Su X Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.
- White E Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
- Morscher RJ University Children's Hospital Zurich, 8032 Zurich, Switzerland.
- Rabinowitz JD Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: joshr@princeton.edu.
- 2020-03-19
Published in:
- Cell metabolism. - 2020
MTHFD2
NAD
NADH
SHMT2
complex I inhibitor
hypoxia
methylene tetrahydrofolate dehydrogenase
mitochondrial disease
redox
respiration inhibition
serine catabolism
serine hydroxymethyltransferase
English
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.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1016/j.cmet.2020.02.017
- PMID 32187526
- Persistent URL
- https://sonar.ch/global/documents/88725
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