Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease
Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD+ to alleviate mitochondrial disease
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DOI：
10.1016/j.cmet.2021.06.013
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发表时间：
2021-10-05
期刊：
影响因子：
29
通讯作者：
Jiang, Hui
中科院分区：
文献类型：
--
作者：
Liu, Shanshan;Fu, Song;Jiang, Hui
电子传递链（ETC）功能障碍或缺氧导致毒性NADH积累。细胞如何在这种条件下再生NAD（+）仍然是难以捉摸的。在这里，结合生物信息学分析和实验验证，我们确定甘油-3-磷酸（Gro 3 P）的生物合成作为内源性NAD（+）-再生途径。在遗传或药理学ETC抑制下，破坏Gro 3 P合成抑制酵母增殖，缩短C. elegans，损害培养物和异种移植物中癌细胞的生长，并导致小鼠肝脏中的代谢紊乱。此外，Gro 3 P穿梭选择性地再生线粒体复合物I抑制下的胞质NAD（+）;增强Gro 3 P合成促进穿梭活性，以恢复复合物I受损细胞的增殖。与其他器官相比，小鼠大脑具有低得多的Gro 3 P合成酶水平。引人注目的是，增强Gro 3 P合成抑制了神经炎症并延长了Ndufs 4（-/-）小鼠的寿命。总的来说，我们的研究结果揭示了Gro 3 P生物合成作为进化上保守的NADH/NAD（+）氧化还原稳态协调者，并提出了线粒体复合物I疾病的治疗靶点。
Electron transport chain (ETC) dysfunction or hypoxia causes toxic NADH accumulation. How cells regenerate NAD(+) under such conditions remains elusive. Here, integrating bioinformatic analysis and experimental validation, we identify glycerol-3-phosphate (Gro3P) biosynthesis as an endogenous NAD(+)-regeneration pathway. Under genetic or pharmacological ETC inhibition, disrupting Gro3P synthesis inhibits yeast proliferation, shortens lifespan of C. elegans, impairs growth of cancer cells in culture and in xenografts, and causes metabolic derangements in mouse liver. Moreover, the Gro3P shuttle selectively regenerates cytosolic NAD(+) under mitochondrial complex I inhibition; enhancing Gro3P synthesis promotes shuttle activity to restore proliferation of complex I-impaired cells. Mouse brain has much lower levels of Gro3P synthesis enzymes as compared with other organs. Strikingly, enhancing Gro3P synthesis suppresses neuroinflammation and extends lifespan in the Ndufs4(-/-) mice. Collectively, our results reveal Gro3P biosynthesis as an evolutionarily conserved coordinator of NADH/NAD(+) redox homeostasis and present a therapeutic target for mitochondrial complex I diseases.