Mahmood, M. et al. (2024) Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma. Nature Cancer, (doi: 10.1038/s43018-023-00721-w) (PMID:38286828) (Early Online Publication)
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Abstract
The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
| Item Type: | Articles |
|---|---|
| Status: | Early Online Publication |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Lilla, Dr Sergio and Tolla, Elisabetta and Tait-Mulder, Dr Jacqueline and Zanivan, Professor Sara and Blyth, Professor Karen and Shergold, Miss Amy and Roberts, Dr Ed and Sumpton, Mr David and Gammage, Dr Payam and Young, Alex and Mahmood, Mahnoor and Huerta Uribe, Mr Alejandro and Mitchell, Mrs Louise |
| Authors: | Mahmood, M., Liu, E. M., Shergold, A. L., Tolla, E., Tait-Mulder, J., Huerta Uribe, A., Shokry, E., Young, A. L., Lilla, S., Kim, M., Park, T., Boscenco, S., Manchon, J. L., Rodríguez-Antona, C., Walters, R. C., Springett, R. J., Blaza, J. N., Mitchell, L., Blyth, K., Zanivan, S., Sumpton, D., Roberts, E. W., Reznik, E., and Gammage, P. A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Nature Cancer |
| Publisher: | Nature Research |
| ISSN: | 2662-1347 |
| ISSN (Online): | 2662-1347 |
| Published Online: | 29 January 2024 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in Nature Cancer 2024 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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