Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma Journal Articles uri icon

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  • AbstractGroup 3 medulloblastoma (G3 MB) carries the worst prognosis of all MB subgroups. MYC oncoprotein is elevated in G3 MB tumors; however, the mechanisms that support MYC abundance remain unclear. Using metabolic and mechanistic profiling, we pinpoint a role for mitochondrial metabolism in regulating MYC. Complex-I inhibition decreases MYC abundance in G3 MB, attenuates the expression of MYC-downstream targets, induces differentiation, and prolongs male animal survival. Mechanistically, complex-I inhibition increases inactivating acetylation of antioxidant enzyme SOD2 at K68 and K122, triggering the accumulation of mitochondrial reactive oxygen species that promotes MYC oxidation and degradation in a mitochondrial pyruvate carrier (MPC)-dependent manner. MPC inhibition blocks the acetylation of SOD2 and oxidation of MYC, restoring MYC abundance and self-renewal capacity in G3 MB cells following complex-I inhibition. Identification of this MPC-SOD2 signaling axis reveals a role for metabolism in regulating MYC protein abundance that has clinical implications for treating G3 MB.


  • Martell, Emma
  • Kuzmychova, Helgi
  • Kaul, Esha
  • Senthil, Harshal
  • Chowdhury, Subir Roy
  • Morrison, Ludivine Coudière
  • Fresnoza, Agnes
  • Zagozewski, Jamie
  • Venugopal, Chitra
  • Anderson, Chris M
  • Singh, Sheila
  • Banerji, Versha
  • Werbowetski-Ogilvie, Tamra E
  • Sharif, Tanveer

publication date

  • May 2, 2023