The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming
Open accessAbstract
T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.
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Cites
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Cited by
Akhtar, A., Shakir, M., Ansari, M. S., Divya, Faizan, M. I., Chauhan, V., Singh, A., Alam, R., Azmi, I., Sharma, S., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102021 · Cited by 21
Li, C., Qin, C., Li, X., Wang, J., Li, Y., & Sun, Q. (2026) · International Journal of Oncology · doi:10.3892/ijo.2026.5845 · Cited by 3
Metadata
- Authors
- Wu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., Ghesquière, B., Theurich, S., Dudek, J., Gasteiger, G., Zernecke, A., Kobold, S., Kastenmüller, W., & Vaeth, M.
- Venue
- Nature Communications
- Published
- 2023-10-27
- Volume
- 14
- Issue
- 1
- Pages
- 6858-6858
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W4387971855
- Cited by
- 322
- References
- 69
- FWCI
- 28.32
- Type
- journal article
- Language
- en
- Open access
- gold
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- Wu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., Ghesquière, B., Theurich, S., Dudek, J., Gasteiger, G., Zernecke, A., Kobold, S., Kastenmüller, W., & Vaeth, M. (2023). Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nature Communications. https://doi.org/10.1038/s41467-023-42634-3
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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