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. https://doi.org/10.1038/s41467-023-38049-9

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

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

• Bioblast editor: Plangger M • O2k-Network Lab: CA Winnipeg Banerji V

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cancer 

Organism: Human  Tissue;cell: Nervous system  Preparation: Permeabilized cells, Intact cells  Enzyme: Complex I 

Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: N, S, CIV, ROX  HRR: Oxygraph-2k 

2023-05