Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain
9 affiliations
- 1Research Unit, Hospital of Santa Cristina, Research Institute La Princesa (IIS Princesa), Hospital de la Princesa, Universidad Autónoma de Madrid, 28009 Madrid, Spain.
- 2Laboratory of Exercise and Health, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), 8603 Zurich, Switzerland.
- 3Laboratory for Orthopaedic Biomechanics, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH), 8008 Zurich, Switzerland.
- 4University Hospital Balgrist, University of Zurich, 8008 Zurich, Switzerland.
- 5Immunology Department, Hospital de la Princesa, Instituto Investigación Sanitaria Princesa (IIS Princesa), 28006 Madrid, Spain.
- 6CIBER de Enfermedades Respiratorias (CIBERES), Carlos III Health Institute, 28029 Madrid, Spain.
- 7CIBER de Enfermedades Cardiovasculares (CIBERCV), Carlos III Health Institute, 28029 Madrid, Spain.
- 8Unidad de Videomicroscopia, Instituto Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain.
- 9Centro Nacional de Investigaciónes Cardiovasculares (CNIC) Carlos III, 28029 Madrid, Spain.
Abstract
Hypoxia-inducible factors (HIFs) are constitutively active in clear cell renal cell carcinoma (ccRCC) cells. Here, we investigated whether these cells could still respond to hypoxia independently of canonical HIF activation. We found that hypoxia provokes a NADH reductive stress that attenuates lactate release when the supply of extracellular pyruvate becomes limited, a response that was restored by the ectopic expression of the cytosolic and mitochondria-targeted NADH oxidase (LbNOX). Suppression of the mitochondrial electron transport chain (mtETC) alone is sufficient to attenuate glycolytic flux when extracellular pyruvate is limited, a situation consistent with metabolomic data from human ccRCCs. Furthermore, this response can be mimicked by pharmacological or genetic inhibition of mitochondrial complex IV (CIV) activity and restored by the mitochondrial-targeted alternative oxidase (AOX). Therefore, our data suggest that cells can respond to low oxygen tension through a mitochondrial-dependent elevation of NADH/NAD⁺, resulting in the suppression of glycolysis when pyruvate availability is compromised.
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BibTeX
@article{guajardogrence2026oxygendependent,
title = {{Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain}},
author = {Andrea Guajardo-Grence and María Fernández-Lamadrid and Greta Moschini and Lidia Marin-Algeciras and Claudia Mesa-Ciller and Rosa Andreu Martínez and Lucía Fernández-Arroyo and Rebeca Vázquez Muñoz and María José Calzada and Noa Beatriz Martín-Cófreces and José Antonio Enríquez and Katrien De Bock and Julián Aragonés},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aed1177},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aed1177},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain
AU - Andrea Guajardo-Grence
AU - María Fernández-Lamadrid
AU - Greta Moschini
AU - Lidia Marin-Algeciras
AU - Claudia Mesa-Ciller
AU - Rosa Andreu Martínez
AU - Lucía Fernández-Arroyo
AU - Rebeca Vázquez Muñoz
AU - María José Calzada
AU - Noa Beatriz Martín-Cófreces
AU - José Antonio Enríquez
AU - Katrien De Bock
AU - Julián Aragonés
PY - 2026
DA - 2026/10/30
JO - Science Advances
DO - 10.1126/sciadv.aed1177
UR - https://www.science.org/doi/abs/10.1126/sciadv.aed1177
AB - Hypoxia-inducible factors (HIFs) are constitutively active in clear cell renal cell carcinoma (ccRCC) cells. Here, we investigated whether these cells could still respond to hypoxia independently of canonical HIF activation. We found that hypoxia provokes a NADH reductive stress that attenuates lactate release when the supply of extracellular pyruvate becomes limited, a response that was restored by the ectopic expression of the cytosolic and mitochondria-targeted NADH oxidase (LbNOX). Suppression of the mitochondrial electron transport chain (mtETC) alone is sufficient to attenuate glycolytic flux when extracellular pyruvate is limited, a situation consistent with metabolomic data from human ccRCCs. Furthermore, this response can be mimicked by pharmacological or genetic inhibition of mitochondrial complex IV (CIV) activity and restored by the mitochondrial-targeted alternative oxidase (AOX). Therefore, our data suggest that cells can respond to low oxygen tension through a mitochondrial-dependent elevation of NADH/NAD⁺, resulting in the suppression of glycolysis when pyruvate availability is compromised.
SN - 2375-2548
ER -