呼吸受損時絲氨酸代謝補充NADH
作者：
小柯機器人發布時間：2020/3/24 11:56:31
近日，美國普林斯頓大學Joshua D. Rabinowitz及其小組的最新研究表明，呼吸受損時絲氨酸代謝補充NADH。 這一研究成果於2020年3月17日在線發表於《細胞—代謝》雜誌。
通過在培養的細胞和小鼠中進行氘示蹤研究，研究人員表明葉酸依賴性絲氨酸分解代謝也可產生大量的NADH。令人驚訝的是，當呼吸受損時，通過亞甲基四氫葉酸脫氫酶（MTHFD2）進行的絲氨酸分解代謝成為主要的NADH來源。在缺氧，二甲雙胍或遺傳性損傷導致呼吸減慢的細胞中，線粒體絲氨酸分解代謝的抑制可部分使NADH水平正常化並促進細胞生長。
在具有工程改造的線粒體複合體I缺乏症（NDUSF4-/-）的小鼠中，絲氨酸對NADH的貢獻增加，並且通過藥理阻斷絲氨酸降解來適度減緩痙攣的進程。因此，當呼吸受損時，絲氨酸分解代謝會導致有毒的NADH積累。
據介紹，NADH為有氧ATP生產提供電子。在缺氧或電子傳輸鏈活性受損的細胞中，NADH的積累可能是有毒的。為了使這種毒性最小化，升高的NADH會抑制經典的NADH產生途徑：葡萄糖、穀氨醯胺和脂肪氧化。
附：英文原文
Title: Serine Catabolism Feeds NADH when Respiration Is Impaired
Author: 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
Issue&Volume: 2020-03-17
Abstract: NADH provides electrons for aerobic ATP production. In cells deprived of oxygen orwith impaired electron transport chain activity, NADH accumulation can be toxic. Tominimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways:glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies incultured cells and mice, we show that folate-dependent serine catabolism also producessubstantial NADH. Strikingly, when respiration is impaired, serine catabolism throughmethylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. Incells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrialserine catabolism inhibition partially normalizes NADH levels and facilitates cellgrowth. In mice with engineered mitochondrial complex I deficiency (NDUSF4/), serine’scontribution to NADH is elevated, and progression of spasticity is modestly slowedby pharmacological blockade of serine degradation. Thus, when respiration is impaired,serine catabolism contributes to toxic NADH accumulation.
DOI: 10.1016/j.cmet.2020.02.017
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30114-5