Serine Catabolism Feeds NADH when Respiration Is Impaired

Yang Lifeng; Canaveras Juan Carlos Garcia; Chen Zihong; Wang Lin; Liang Lingfan; Jang Cholsoon; Mayr Johannes A.; Zhang Zhaoyue; Ghergurovich Jonathan M.; Zhan Le; Joshi Shilpy; Hu Zhixian; McReynolds Melanie R.; Su Xiaoyang; White Eileen; Morscher Raphael J.; Rabinowitz Joshua D.

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Serine Catabolism Feeds NADH when Respiration Is Impaired

机译：呼吸损害时丝氨酸分解代谢喂养NADH

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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, mitochondria! serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondria! 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.

机译：NADH为有氧ATP生产提供电子。在被剥夺氧气的细胞或电子传输链活性受损的细胞中，NADH积累可能是有毒的。为了使这种毒性最小化，升高的NADH抑制了典型的NADH产生途径：葡萄糖，谷氨酰胺和脂肪氧化。这里，通过培养细胞和小鼠的氘跟踪研究，我们表明叶酸依赖性丝氨酸脱蛋白也产生了大量的纳米。惊人的是，当呼吸受损时，通过亚甲基四氢溶酯脱氢酶（MTHFD2）的丝氨酸分解代谢成为主要的NADH源。在呼吸呼吸缺氧，二甲双胍或遗传病变，线粒体的细胞中！丝氨酸分解代谢抑制部分归一化NADH水平并促进细胞生长。在与工程化线粒体的小鼠！ Complex I缺陷（Ndusf4 - / - ），丝氨酸对NADH的贡献升高，痉挛的进展是由丝氨酸降解的药理学阻滞急剧减慢。因此，当呼吸受到损害时，丝氨酸分解代谢有助于毒性纳米积累。

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《Cell metabolism》 |2020年第4期|共19页
作者
Yang Lifeng; Canaveras Juan Carlos Garcia; Chen Zihong; Wang Lin; Liang Lingfan; Jang Cholsoon; Mayr Johannes A.; Zhang Zhaoyue; Ghergurovich Jonathan M.; Zhan Le; Joshi Shilpy; Hu Zhixian; McReynolds Melanie R.; Su Xiaoyang; White Eileen; Morscher Raphael J.; Rabinowitz Joshua D.;
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Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Tsinghua Univ Sch Pharmaceut Sci Beijing 100084 Peoples R China;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Salzburger Landeskliniken Dept Pediat A-5020 Salzburg Austria;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Rutgers Canc Inst New Jersey New Brunswick NJ 08903 USA;

Rutgers Canc Inst New Jersey New Brunswick NJ 08903 USA;

Rutgers Canc Inst New Jersey New Brunswick NJ 08903 USA;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

Rutgers Canc Inst New Jersey New Brunswick NJ 08903 USA;

Rutgers Canc Inst New Jersey New Brunswick NJ 08903 USA;

Univ Childrens Hosp Zurich CH-8032 Zurich Switzerland;

Princeton Univ Lewis Sigler Inst Integrat Genom Princeton NJ 08544 USA;

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中图分类内分泌腺疾病及代谢病;
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1. Serine Catabolism Feeds NADH when Respiration Is Impaired [J] . Yang Lifeng, Canaveras Juan Carlos Garcia, Chen Zihong, Cell metabolism . 2020,第4期

机译：呼吸损害时丝氨酸分解代谢喂养NADH
2. Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: Involvement of mitochondrial glutamate metabolism [J] . MeloD.R., MirandolaS.R., Assun??oN.A., Journal of Neuroscience Research . 2012,第6期

机译：丙二酸甲酯削弱了NADH相关底物支持的线粒体呼吸作用：涉及线粒体谷氨酸代谢
3. Methylmalonate impairs mitochondrial respiration supported by NADH-linked substrates: Involvement of mitochondrial glutamate metabolism [J] . MeloD.R., MirandolaS.R., Assun??oN.A., Journal of Neuroscience Research . 2012,第6期

机译：甲基丙酸酯损害NADH连接基材支持的线粒体呼吸：线粒体谷氨酸代谢的累积
4. Normal mode assignment of crystalline DL- and L-serine, L-phospho-serine and Calcium phospho-serine [C] . Shigeru Sasaki, Jan T. Czernuszka, Hazel E. Assender 日本材料強度学会学術講演会 . 2009

机译：结晶DL-和L-丝氨酸，L-磷酸丝氨酸和钙丝氨酸的正常模式分配
5. Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal: A mechanism of free radical mediated mitochondrial dysfunction. [D] . Humphries, Kenneth Michael. 2000

机译：4-羟基-2-壬烯醛抑制NADH连锁的线粒体呼吸：自由基介导的线粒体功能障碍的机制。
6. Engineering a synthetic anaerobic respiration for reduction of xylose to xylitol using NADH output of glucose catabolism by Escherichia coli AI21 [O] . Andrew Iverson, Erin Garza, Ryan Manow, 2016

机译：使用大肠杆菌AI21的葡萄糖分解代谢的NADH输出设计合成厌氧呼吸以将木糖还原为木糖醇
7. Engineering a synthetic anaerobic respiration for reduction of xylose to xylitol using NADH output of glucose catabolism by AI21 [O] . 2016

机译：利用AI21的葡萄糖分解代谢的NADH输出工程化合成厌氧呼吸以将木糖还原为木糖醇

Serine Catabolism Feeds NADH when Respiration Is Impaired

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