Complex I Drives Glutamine-Dependent TCA Cycle to Support Viability of MYChighBreast Cancer Cells

  1. Johanna M. Anttila
  2. Mariel Savelius
  3. Juhi Somani
  4. Daniel Nicorici
  5. Pauliina M. Munne
  6. Linda Id
  7. Aino Peura
  8. Antti O. Hiltunen
  9. July Aung
  10. Ryan Awadhpersad
  11. Bina Prajapati
  12. Martina Peltonen
  13. Hanna Ala-Hongisto
  14. Prson Gautam
  15. Mika J. VÀlimÀki
  16. Topi A. Tervonen
  17. Karina Ơapovalovaitė
  18. Raman Devarajan
  19. MarĂ­a Victoria Ruiz PĂ©rez
  20. Minna Mutka
  21. Panu Kovanen
  22. Laura Niinikoski
  23. Tuomo Meretoja
  24. Johanna Mattson
  25. PÀivi HeikkilÀ
  26. Krister Wennerberg
  27. Marie Arsenian-Henriksson
  28. Jukka Westermarck
  29. Tero Aittokallio
  30. Andrei Goga
  31. Christopher B. Jackson
  32. Anni I. Nieminen
  33. Juha Klefström
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Abstract

In many cancers, stably elevated MYC levels drive persistent and concerted activation of cell growth promoting anabolic programs and the cell cycle in ways that are distinct from normal cells. Therefore, synthetic-lethal strategies to target MYC reprograming of these pathways may identify new selective anticancer therapies for the treatment of MYChightumors. Here, we identify enhanced mitochondrial respiration as a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+through complex I-mediated oxidation of NADH. Metabolic carbon tracing analysis revealed that MYC shifts TCA cycle’s carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors resulted in MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChightumors, persistent inhibition of tumor growth was achieved through combined inhibition of complex I and glutaminolysis. Our results suggest that the high respiration rate observed in MYChighcells supports glutamine carbon-enriched TCA cycle, rendering MYChightumors selectively vulnerable to inhibitors of mitochondrial respiration and glutaminolysis.

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