Oxygen-dependent constraint of glycolysis through the mitochondrial electron transport chain
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 ( Lb NOX). 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.
Authors
- Andrea Guajardo-Grence (ORCID: https://orcid.org/0000-0002-4437-8529)
- Julián Aragonés (ORCID: https://orcid.org/0000-0002-0193-4679)
- José Antonio Enrı́quez (ORCID: https://orcid.org/0000-0002-3671-2961)
- Katrien De Bock (ORCID: https://orcid.org/0000-0001-8232-4663)
- María José Calzada (ORCID: https://orcid.org/0000-0001-8615-960X)
- Claudia Mesa‐Ciller (ORCID: https://orcid.org/0000-0001-9807-5550)
- Noa Beatriz Martin-Cofreces (ORCID: https://orcid.org/0000-0003-0439-8979)
- Lucía Fernández-Arroyo (ORCID: https://orcid.org/0000-0001-9229-8470)
- Greta Moschini (ORCID: https://orcid.org/0000-0002-9845-9965)
- Rosa Andreu-Martínez (ORCID: https://orcid.org/0000-0002-2553-7344)
- Lidia Marín Algeciras (ORCID: https://orcid.org/0009-0008-4749-3048)
- María Fernández-Lamadrid
- Rebeca Vázquez Muñoz (ORCID: https://orcid.org/0009-0000-6454-6924)
Institutions
- University of Zurich (CH)
- Instituto de Salud Carlos III (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- ETH Zurich (CH)
- Centro de Investigación en Red en Enfermedades Cardiovasculares (ES)
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES)
- Centro de Investigación Biomédica en Red (ES)
- Universitätsklinik Balgrist (CH)
- Hospital Universitario de La Princesa (ES)
- Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1126/sciadv.aed1177
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Comunidad de Madrid
- Ministerio de Ciencia, Innovación y Universidades
- Universidad Autónoma de Madrid
- Ministerio de Ciencia e Innovación
- Instituto de Salud Carlos III