4.8 Article

A hydride transfer complex reprograms NAD metabolism and bypasses senescence

期刊

MOLECULAR CELL
卷 81, 期 18, 页码 3848-+

出版社

CELL PRESS
DOI: 10.1016/j.molcel.2021.08.028

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资金

  1. CIHR [MOP11151, PJT-153217, MOP130414, MOP-133726]
  2. CCSRI Innovation [706773]
  3. TFF Oncometabolism Team Grant [239585]
  4. CIBC chair for breast cancer research
  5. NSER CCREATE Trainee program
  6. FRQS (Fonds de Recherche du Quebec-Sante)
  7. CIHR Postdoctoral Fellowship [MFE-171312]
  8. FRQS
  9. Max Kade fellowship fromthe Austrian Academy of Sciences
  10. FRQS Senior award
  11. FRQS Junior 1 award
  12. Canadian Institutes of Health Research grant [CIHRMOP-110972]
  13. Canada Research Chair in Calcified tissues, Biomaterials and Structural Imaging
  14. COMET Competence CenterCBmed-Center for Biomarker Research in Medicine [FA791A0906.FFG]
  15. Austrian Federal Ministry for Transport, Innovation and Technology (BMVIT)
  16. Austrian Federal Ministry for Digital and Economic Affairs (BMDW)
  17. Land Steiermark (Department 12, Business and Innovation)
  18. Styrian Business Promotion Agency (SFG)
  19. Vienna Business Agency
  20. FWF [P26011]
  21. Christian Doppler Laboratory for AppliedMetabolomics
  22. Austrian Federal Ministry for Transport, Innovation and Technology
  23. National Foundation for Research, Technology and Development
  24. Austrian Science Funds [SFB-F4707, SFB-F06107]
  25. EU Transcan-2 consortium ERANET-PLL via the Austrian Science Funds
  26. ICM (Institut du cancer de Montreal) Canderel fellowship

向作者/读者索取更多资源

A multi-enzymatic complex, known as hydride transfer complex (HTC), is reported to reprogram NAD metabolism and overcome cellular senescence in cancer or hypoxic cells. This complex is highly expressed in prostate cancer models and its inactivation triggers senescence, while its exogenous expression can bypass senescence and cooperate with oncogenic RAS to transform primary cells.
Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP(+). This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.

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