Serine Catabolism Feeds NADH when Respiration Is Impaired.

TitleSerine Catabolism Feeds NADH when Respiration Is Impaired.
Publication TypeJournal Article
Year of Publication2020
AuthorsYang, L, Canaveras, JCarlos Gar, Chen, Z, Wang, L, Liang, L, Jang, C, Mayr, JA, Zhang, Z, Ghergurovich, JM, Zhan, L, Joshi, S, Hu, Z, McReynolds, MR, Su, X, White, E, Morscher, RJ, Rabinowitz, JD
JournalCell Metab
Date Published2020 Apr 07
KeywordsAnimals, Cell Hypoxia, Cell Line, Humans, Mice, Mice, Inbred C57BL, Mice, Nude, Mitochondria, NAD, Oxygen, Serine

<p>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.</p>

Alternate JournalCell Metab
PubMed ID32187526
PubMed Central IDPMC7397714
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA130893 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States