Serine Catabolism Feeds NADH when Respiration Is Impaired

Cell Metab. 2020 Apr 7;31(4):809-821.e6. doi: 10.1016/j.cmet.2020.02.017. Epub 2020 Mar 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia*
  • Cell Line
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mitochondria / metabolism*
  • NAD / metabolism*
  • Oxygen / metabolism*
  • Serine / metabolism*


  • NAD
  • Serine
  • Oxygen