Serine Catabolism Feeds NADH when Respiration Is Impaired.,Cell Metabolism

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Serine Catabolism Feeds NADH when Respiration Is Impaired.
Cell Metabolism ( IF 27.7 ) Pub Date : 2020-03-17 , DOI: 10.1016/j.cmet.2020.02.017
Lifeng Yang ₁ , Juan Carlos Garcia Canaveras ₁ , Zihong Chen ₁ , Lin Wang ₁ , Lingfan Liang ₂ , Cholsoon Jang ₁ , Johannes A Mayr ₃ , Zhaoyue Zhang ₁ , Jonathan M Ghergurovich ₄ , Le Zhan ₅ , Shilpy Joshi ₅ , Zhixian Hu ₅ , Melanie R McReynolds ₁ , Xiaoyang Su ₆ , Eileen White ₇ , Raphael J Morscher ₈ , Joshua D Rabinowitz ₉

Affiliation

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.
Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg 5020, Austria.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
University Children's Hospital Zurich, 8032 Zurich, Switzerland.
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

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.

中文翻译：

当呼吸受损时，丝氨酸分解代谢为 NADH 提供营养。

NADH 为有氧 ATP 生产提供电子。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。为了尽量减少这种毒性，升高的 NADH 会抑制经典的 NADH 产生途径：葡萄糖、谷氨酰胺和脂肪氧化。在这里，通过对培养细胞和小鼠的氘追踪研究，我们表明叶酸依赖性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) 进行的丝氨酸分解代谢成为 NADH 的主要来源。在呼吸因缺氧、二甲双胍或遗传病变而减慢的细胞中，线粒体丝氨酸分解代谢抑制使 NADH 水平部分正常化并促进细胞生长。在患有工程化线粒体复合物 I 缺陷 (NDUSF4-/-) 的小鼠中，丝氨酸' 对 NADH 的贡献增加，并且通过药物阻断丝氨酸降解适度减缓痉挛的进展。因此，当呼吸受损时，丝氨酸分解代谢会导致有毒的 NADH 积累。

更新日期：2020-04-20

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