Glycerol-3-phosphate biosynthesis regenerates cytosolic NAD + to alleviate mitochondrial disease

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

Cell & Developmental Bio, Biochemistry, MetabolismNicholas Liao2021-10 (Oct)