Mitochondrial metabolism and cancer therapeutic innovation
Abstract Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes crit...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-08-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02311-x |
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| _version_ | 1849761064798912512 |
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| author | Hongxiang Du Tianhan Xu Sihui Yu Sufang Wu Jiawen Zhang |
| author_facet | Hongxiang Du Tianhan Xu Sihui Yu Sufang Wu Jiawen Zhang |
| author_sort | Hongxiang Du |
| collection | DOAJ |
| description | Abstract Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions. |
| format | Article |
| id | doaj-art-c6dfb240c0984f23876af14046fbaea0 |
| institution | DOAJ |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-c6dfb240c0984f23876af14046fbaea02025-08-20T03:06:09ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-08-0110113710.1038/s41392-025-02311-xMitochondrial metabolism and cancer therapeutic innovationHongxiang Du0Tianhan Xu1Sihui Yu2Sufang Wu3Jiawen Zhang4Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Obstetrics and Gynecology, Zhongshan Hospital, Fudan UniversityDepartment of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineAbstract Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions.https://doi.org/10.1038/s41392-025-02311-x |
| spellingShingle | Hongxiang Du Tianhan Xu Sihui Yu Sufang Wu Jiawen Zhang Mitochondrial metabolism and cancer therapeutic innovation Signal Transduction and Targeted Therapy |
| title | Mitochondrial metabolism and cancer therapeutic innovation |
| title_full | Mitochondrial metabolism and cancer therapeutic innovation |
| title_fullStr | Mitochondrial metabolism and cancer therapeutic innovation |
| title_full_unstemmed | Mitochondrial metabolism and cancer therapeutic innovation |
| title_short | Mitochondrial metabolism and cancer therapeutic innovation |
| title_sort | mitochondrial metabolism and cancer therapeutic innovation |
| url | https://doi.org/10.1038/s41392-025-02311-x |
| work_keys_str_mv | AT hongxiangdu mitochondrialmetabolismandcancertherapeuticinnovation AT tianhanxu mitochondrialmetabolismandcancertherapeuticinnovation AT sihuiyu mitochondrialmetabolismandcancertherapeuticinnovation AT sufangwu mitochondrialmetabolismandcancertherapeuticinnovation AT jiawenzhang mitochondrialmetabolismandcancertherapeuticinnovation |