Ubiquinol-mediated suppression of mitochondria-associated ferroptosis is a targetable function of lactate dehydrogenase B in cancer

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 () and Thomas Michael Marti ()
Additional contact information
Haibin Deng: Central South University
Liang Zhao: Bern University Hospital
Huixiang Ge: Bern University Hospital
Yanyun Gao: Bern University Hospital
Yan Fu: Bern University Hospital
Yantang Lin: Bern University Hospital
Mojgan Masoodi: Bern University Hospital
Tereza Losmanova: University of Bern
Michaela Medová: Central South University
Julien Ott: Bern University Hospital
Min Su: Central South University
Wenxiang Wang: Central South University
Ren-Wang Peng: Bern University Hospital
Patrick Dorn: Bern University Hospital
Thomas Michael Marti: Bern University Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57906-3

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