Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
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 regu...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38049-9 |
| _version_ | 1797832020221493248 |
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| author | 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 Tanveer Sharif |
| author_facet | 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 Tanveer Sharif |
| author_sort | Emma Martell |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T14:01:02Z |
| format | Article |
| id | doaj.art-5c5a7943a1a04bfc88a6392559029355 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T14:01:02Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-5c5a7943a1a04bfc88a63925590293552023-05-07T11:18:11ZengNature PortfolioNature Communications2041-17232023-05-0114112610.1038/s41467-023-38049-9Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastomaEmma Martell0Helgi Kuzmychova1Esha Kaul2Harshal Senthil3Subir Roy Chowdhury4Ludivine Coudière Morrison5Agnes Fresnoza6Jamie Zagozewski7Chitra Venugopal8Chris M. Anderson9Sheila K. Singh10Versha Banerji11Tamra E. Werbowetski-Ogilvie12Tanveer Sharif13Department of Pathology, Rady Faculty of Health Sciences, University of ManitobaDepartment of Pathology, Rady Faculty of Health Sciences, University of ManitobaFaculty of Science, University of ManitobaDepartment of Pathology, Rady Faculty of Health Sciences, University of ManitobaCancerCare ManitobaDepartment of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaCentral Animal Care Services, University of ManitobaDepartment of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaMcMaster Stem Cell and Cancer Research Institute, McMaster UniversityNeuroscience Research Program, Kleysen Institute for Advanced Medicine, Health Sciences CentreMcMaster Stem Cell and Cancer Research Institute, McMaster UniversityCancerCare ManitobaDepartment of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of ManitobaDepartment of Pathology, Rady Faculty of Health Sciences, University of ManitobaAbstract 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.https://doi.org/10.1038/s41467-023-38049-9 |
| spellingShingle | 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 Tanveer Sharif Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma Nature Communications |
| title | Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma |
| title_full | Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma |
| title_fullStr | Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma |
| title_full_unstemmed | Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma |
| title_short | Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma |
| title_sort | metabolism based targeting of myc via mpc sod2 axis mediated oxidation promotes cellular differentiation in group 3 medulloblastoma |
| url | https://doi.org/10.1038/s41467-023-38049-9 |
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