Martell 2023 Nat Commun

Martell E, Kuzmychova H, Kaul E, Senthil H, Chowdhury SR, Morrison LC, Fresnoza A, Zagozewski J, Venugopal C, Anderson CM, Singh SK, Banerji V, Werbowetski-Ogilvie TE, Sharif T (2023) Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma.

» Nat Commun 14:2502. PMID: 37130865 Open Access

Martell E, Kuzmychova H, Kaul E, Senthil H, Chowdhury SR, Morrison LC, Fresnoza A, Zagozewski J, Venugopal C, Anderson CM, Singh SK, Banerji V, Werbowetski-Ogilvie TE, Sharif T (2023) Nat Commun

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.

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2023-05