Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
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.
NADH 为需氧 ATP 生成提供电子。在缺氧或电子传递链活性受损的细胞中，NADH 的积累可能是有毒的。为了最大程度地减少这种毒性，升高的 NADH 会抑制经典的 NADH 生成途径：葡萄糖、谷氨酰胺和脂肪氧化。在这里，通过培养细胞和小鼠中的氘示踪研究，我们表明依赖于叶酸的丝氨酸分解代谢也会产生大量的 NADH。引人注目的是，当呼吸受损时，通过亚甲基四氢叶酸脱氢酶 (MTHFD2) 的丝氨酸分解代谢成为主要的 NADH 来源。在呼吸因缺氧、二甲双胍或遗传缺陷而减慢的细胞中，线粒体丝氨酸分解代谢的抑制部分使 NADH 水平正常化，并促进细胞生长。在工程化的线粒体复合物 I 缺陷（NDUSF4-/-）小鼠中，丝氨酸对 NADH 的贡献增加，通过抑制丝氨酸降解，痉挛的进展适度减缓。因此，当呼吸受损时，丝氨酸分解代谢会导致有毒的 NADH 积累。
