Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer
Abstract Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB’s role in countering mitochondria-associated ferroptosis independently of lactate’s function as a carbon source. LDHB silencing alters mitochondrial morphology,...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57906-3 |
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| author | Haibin Deng Liang Zhao Huixiang Ge Yanyun Gao Yan Fu Yantang Lin Mojgan Masoodi Tereza Losmanova Michaela Medová Julien Ott Min Su Wenxiang Wang Ren-Wang Peng Patrick Dorn Thomas Michael Marti |
| author_facet | Haibin Deng Liang Zhao Huixiang Ge Yanyun Gao Yan Fu Yantang Lin Mojgan Masoodi Tereza Losmanova Michaela Medová Julien Ott Min Su Wenxiang Wang Ren-Wang Peng Patrick Dorn Thomas Michael Marti |
| author_sort | Haibin Deng |
| collection | DOAJ |
| description | Abstract Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB’s role in countering mitochondria-associated ferroptosis independently of lactate’s function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies. |
| format | Article |
| id | doaj-art-71dde92752824cfe97190c44dd71465e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-71dde92752824cfe97190c44dd71465e2025-08-20T02:56:09ZengNature PortfolioNature Communications2041-17232025-03-0116111710.1038/s41467-025-57906-3Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancerHaibin Deng0Liang Zhao1Huixiang Ge2Yanyun Gao3Yan Fu4Yantang Lin5Mojgan Masoodi6Tereza Losmanova7Michaela Medová8Julien Ott9Min Su10Wenxiang Wang11Ren-Wang Peng12Patrick Dorn13Thomas Michael Marti142nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalInstitute of Clinical Chemistry, Inselspital, Bern University HospitalInstitute of Tissue Medicine and Pathology, ITMP, University of BernHunan Clinical Medical Research Center of Accurate Diagnosis and Treatment for esophageal carcinoma, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityDepartment of Radiation Oncology, Inselspital, Bern University Hospital2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South UniversityDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalDepartment of General Thoracic Surgery, Inselspital, Bern University HospitalAbstract Lactate dehydrogenase B (LDHB) fuels oxidative cancer cell metabolism by converting lactate to pyruvate. This study uncovers LDHB’s role in countering mitochondria-associated ferroptosis independently of lactate’s function as a carbon source. LDHB silencing alters mitochondrial morphology, causes lipid peroxidation, and reduces cancer cell viability, which is potentiated by the ferroptosis inducer RSL3. Unlike LDHA, LDHB acts in parallel with glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH) to suppress mitochondria-associated ferroptosis by decreasing the ubiquinone (coenzyme Q, CoQ) to ubiquinol (CoQH2) ratio. Indeed, supplementation with mitoCoQH2 (mitochondria-targeted analogue of CoQH2) suppresses mitochondrial lipid peroxidation and cell death after combined LDHB silencing and RSL3 treatment, consistent with the presence of LDHB in the cell fraction containing the mitochondrial inner membrane. Addressing the underlying molecular mechanism, an in vitro NADH consumption assay with purified human LDHB reveals that LDHB catalyzes the transfer of reducing equivalents from NADH to CoQ and that the efficiency of this reaction increases by the addition of lactate. Finally, radiation therapy induces mitochondrial lipid peroxidation and reduces tumor growth, which is further enhanced when combined with LDHB silencing. Thus, LDHB-mediated lactate oxidation drives the CoQ-dependent suppression of mitochondria-associated ferroptosis, a promising target for combination therapies.https://doi.org/10.1038/s41467-025-57906-3 |
| spellingShingle | Haibin Deng Liang Zhao Huixiang Ge Yanyun Gao Yan Fu Yantang Lin Mojgan Masoodi Tereza Losmanova Michaela Medová Julien Ott Min Su Wenxiang Wang Ren-Wang Peng Patrick Dorn Thomas Michael Marti Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer Nature Communications |
| title | Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer |
| title_full | Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer |
| title_fullStr | Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer |
| title_full_unstemmed | Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer |
| title_short | Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer |
| title_sort | ubiquinol mediated suppression of mitochondria associated ferroptosis is a targetable function of lactate dehydrogenase b in cancer |
| url | https://doi.org/10.1038/s41467-025-57906-3 |
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