SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes
Succinate, a mitochondrial metabolite, also functions as an extracellular signal through its receptor succinate receptor 1 (SUCNR1), coordinating responses to nutrient availability. The physiological role of SUCNR1 within hepatocytes, however, is unclear. We show that hepatic succinate levels and Sucnr1 expression are dynamically regulated by nutritional status. Mice lacking Sucnr1 in hepatocytes [Hep- Sucnr1 knockout (KO)] exhibit a fasting-like phenotype characterized by enhanced gluconeogenesis, elevated amino acids, and impaired metabolic flexibility. Mechanistically, loss of Sucnr1 compromises glucose-derived oxidative flux through the tricarboxylic acid cycle, increases reliance on glutamine-dependent anaplerosis, and induces mitochondrial stress adaptations. Upon refeeding, Hep- Sucnr1 KO mice show blunted mammalian target of rapamycin activation, incomplete glycogen restoration, and an altered hepatic proteomic response. Sucnr1 expression increases during liver maturation, is enriched in pericentral hepatocytes, and its loss is associated with functional reprogramming of pericentral metabolic functions without disruption of zonation. Together, our findings establish SUCNR1 as a critical regulator of hepatic metabolic adaptation, linking succinate signaling to mitochondrial flexibility and nutrient-dependent metabolic responses.
Authors
- Ana Madeira (ORCID: https://orcid.org/0000-0003-3186-359X)
- Catalina Núñez‐Roa (ORCID: https://orcid.org/0000-0003-2764-5610)
- Ana Belén Plata-Gómez (ORCID: https://orcid.org/0000-0002-6256-0084)
- Rubén Nogueiras (ORCID: https://orcid.org/0000-0002-9976-9930)
- Joan Carles Escolà‐Gil (ORCID: https://orcid.org/0000-0001-9021-2485)
- Óscar Yanes (ORCID: https://orcid.org/0000-0003-3695-7157)
- Jordi Gracia‐Sancho (ORCID: https://orcid.org/0000-0001-7736-4089)
- Joan Josep Vendrell (ORCID: https://orcid.org/0000-0002-6994-6115)
- Alejo Efeyan (ORCID: https://orcid.org/0000-0002-3806-6799)
- Joan R. Badia
- Sonia Fernández‐Veledo (ORCID: https://orcid.org/0000-0003-2906-3788)
- Marc Beltrà (ORCID: https://orcid.org/0000-0001-6070-9861)
- António Zorzano (ORCID: https://orcid.org/0000-0002-1638-0306)
- Jordi Capellades (ORCID: https://orcid.org/0000-0002-6502-8202)
- M‐Mar Rodríguez‐Peña (ORCID: https://orcid.org/0000-0003-2553-9769)
- Victòria Ceperuelo‐Mallafré (ORCID: https://orcid.org/0000-0002-4460-9761)
- Maria Repollés-de-Dalmau (ORCID: https://orcid.org/0000-0003-1402-0611)
- Anna Marsal-Beltran (ORCID: https://orcid.org/0000-0001-9521-6522)
- Eva Nóvoa (ORCID: https://orcid.org/0000-0002-6708-5382)
- Laura Salmerón-Pelado
- Aleix Ribas-Latre
Institutions
- University of Bern (CH)
- University Hospital of Bern (CH)
- Instituto de Salud Carlos III (ES)
- Hospital de Sant Pau (ES)
- Spanish National Cancer Research Centre (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Institut de Recerca Biomèdica Catalunya Sud (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Institute for Research in Biomedicine (ES)
- Institut d'Investigacions Biomèdiques de Barcelona (ES)
- Institut Català d'Arqueologia Clàssica (ES)
- Universitat Rovira i Virgili (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Science Advances
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1126/sciadv.aec8873
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministerio de Ciencia, Innovación y Universidades
- European Commission
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Universitat de Barcelona
- Universitat Rovira i Virgili
- Societat Catalana de Digestologia
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- European Regional Development Fund
- European Social Fund