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Merck

Serine Catabolism Feeds NADH when Respiration Is Impaired.

Cell metabolism (2020-03-19)
Lifeng Yang, Juan Carlos Garcia Canaveras, Zihong Chen, Lin Wang, Lingfan Liang, Cholsoon Jang, Johannes A Mayr, Zhaoyue Zhang, Jonathan M Ghergurovich, Le Zhan, Shilpy Joshi, Zhixian Hu, Melanie R McReynolds, Xiaoyang Su, Eileen White, Raphael J Morscher, Joshua D Rabinowitz
RESUMO

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.

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Sigma-Aldrich
Soro bovino fetal, USA origin, sterile-filtered, suitable for cell culture, suitable for hybridoma
Sigma-Aldrich
βDinucleotídeo de β-nicotinamida e adenina, reduzido, ≥97% (HPLC)
Sigma-Aldrich
ββ-Dinucleotídeo de nicotinamida adenina
Sigma-Aldrich
Malic Dehydrogenase from porcine heart, ≥600 units/mg protein (biuret), ammonium sulfate suspension