Serine Catabolism Feeds NADH when Respiration Is Impaired
Authors/Creators
- 1. Princeton University
- 2. Tsinghua University
- 3. Salzburger Landeskliniken and Paracelsus Medical University
- 4. Rutgers Cancer Institute of New Jersey,
- 5. Rutgers Rutgers Cancer Institute of New Jersey,Institute of New Jersey,
- 6. University Children's Hospital Zurich
Description
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.
Files
Yang et al 2020_authormanuscript.pdf
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(3.0 MB)
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