Cell Metab. 2021 Oct 5;33(10):1974-1987.e9. doi: 10.1016/j.cmet.2021.06.013. | PubMed

Shanshan Liu¹, Song Fu¹, Guodong Wang², Yu Cao³, Lanlan Li³, Xuemei Li⁴, Jun Yang⁵, Ning Li⁶, Yabing Shan⁷, Yang Cao⁷, Yan Ma⁷, Mengqiu Dong⁸, Qinghua Liu⁹, Hui Jiang¹⁰

1. Graduate School of Peking Union Medical College, Beijing 100730, China; National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China.
2. Graduate School of Peking Union Medical College, Beijing 100730, China; National Institute of Biological Sciences, Beijing 102206, China.
3. National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China; College of Life Sciences, Beijing Normal University, Beijing 100875, China.
4. National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China.
5. National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
6. National Institute of Biological Sciences, Beijing 102206, China; College of Life Sciences, China Agriculture University, Beijing 100094, China.
7. National Institute of Biological Sciences, Beijing 102206, China.
8. National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
9. National Institute of Biological Sciences, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China.
10. Graduate School of Peking Union Medical College, Beijing 100730, China; National Institute of Biological Sciences, Beijing 102206, China; Beijing Key Laboratory of Cell Biology for Animal Aging, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 102206, China. Electronic address: jianghui@nibs.ac.cn.

Abstract

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.

Presented By Shanshan Liu | ORCID iD