@article{2613, author = {Lifeng Yang and Juan Canaveras and Zihong Chen and Lin Wang and Lingfan Liang and Cholsoon Jang and Johannes Mayr and Zhaoyue Zhang and Jonathan Ghergurovich and Le Zhan and Shilpy Joshi and Zhixian Hu and Melanie McReynolds and Xiaoyang Su and Eileen White and Raphael Morscher and Joshua Rabinowitz}, title = {Serine Catabolism Feeds NADH when Respiration Is Impaired.}, 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\&$\#$39;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.
}, year = {2020}, journal = {Cell Metab}, volume = {31}, pages = {809-821.e6}, month = {04/2020}, issn = {1932-7420}, doi = {10.1016/j.cmet.2020.02.017}, language = {eng}, }