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

Emma Martell, Helgi Kuzmychova, Esha Kaul, Harshal Senthil, Subir Roy Chowdhury, Ludivine Coudière Morrison, Agnes Fresnoza, Jamie Zagozewski, Chitra Venugopal, Chris M. Anderson, Sheila K. Singh, Versha Banerji, Tamra E. Werbowetski-Ogilvie and Tanveer Sharif ()
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Emma Martell: University of Manitoba
Helgi Kuzmychova: University of Manitoba
Esha Kaul: University of Manitoba
Harshal Senthil: University of Manitoba
Subir Roy Chowdhury: CancerCare Manitoba
Ludivine Coudière Morrison: University of Manitoba
Agnes Fresnoza: University of Manitoba
Jamie Zagozewski: University of Manitoba
Chitra Venugopal: McMaster University
Chris M. Anderson: Health Sciences Centre
Sheila K. Singh: McMaster University
Versha Banerji: CancerCare Manitoba
Tamra E. Werbowetski-Ogilvie: University of Manitoba
Tanveer Sharif: University of Manitoba

Nature Communications, 2023, vol. 14, issue 1, 1-26

Abstract: Abstract Group 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.

Date: 2023
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DOI: 10.1038/s41467-023-38049-9

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