Mitochondrial DNA mutations are present in over 50% of all cancers, and truncating mutations in several genes encoding components of complex I of the respiratory chain are most recurrent. We found that these mutations are a source of Warburg-like metabolic shifts that promote a pro-inflammatory immunological state, enhancing sensitivity to checkpoint blockade.
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References
Kim, M., Mahmood, M., Reznik, E. & Gammage, P. A. Mitochondrial DNA is a major source of driver mutations in cancer. Trends Cancer 8, 1046–1059 (2022). This review is on the role of mtDNA mutations in cancer.
Gorelick, A. N. et al. Respiratory complex and tissue lineage drive recurrent mutations in tumor mtDNA. Nat. Metab. 3, 558–570 (2021). This paper reports incidence and patterns of mtDNA mutation burden across cancer lineages.
Mok, B. Y. et al. A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing. Nature 583, 631–637 (2020). This paper describes the mtDNA-editing technology applied in our study.
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949 (2017). This is a source of immunotherapy data for patients with metastatic melanoma stratified by mtDNA status.
Titov, D. V. et al. Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio. Science 352, 231–235 (2016). This paper describes the effects of NADH oxidase from L. brevis on cellular metabolism.
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This is a summary of: Mahmood, M. et al. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nat. Cancer https://doi.org/10.1038/s43018-023-00721-w (2024).
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Mitochondrial DNA mutation enhances sensitivity to immunotherapy in melanoma. Nat Cancer 5, 544–545 (2024). https://doi.org/10.1038/s43018-023-00722-9
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DOI: https://doi.org/10.1038/s43018-023-00722-9
