2. Academic Validation
  3. SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes

SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes

  • Sci Adv. 2026 Jun 12;12(24):eaec8873. doi: 10.1126/sciadv.aec8873.
Anna Marsal-Beltran 1 2 3,  Laura Salmerón-Pelado 1 2 3,  Aleix Ribas-Latre 1 2,  Maria Repollés-de-Dalmau 1 2 3,  M-Mar Rodríguez-Peña 1 2,  Catalina Núñez-Roa 1 2,  Joan Badia 4,  Ana Madeira 1 2,  Eva Novoa 5 6,  Marc Beltrà 2 7 8,  Ana Belén Plata-Gómez 9,  Jordi Capellades 1 2,  Joan Carles Escolà-Gil 2 10,  Antonio Zorzano 2 7 8,  Óscar Yanes 2 11,  Alejo Efeyan 9,  Ruben Nogueiras 5 6,  Jordi Gracia-Sancho 12 13 14,  Joan Vendrell 1 2 3,  Victòria Ceperuelo-Mallafré 1 2 3,  Sonia Fernández-Veledo 1 2 3
Affiliations

Affiliations

  • 1 Institut de Recerca Biomèdica Catalunya Sud (formerly Institut d'Investigació Sanitària Pere Virgili), Hospital Universitari Joan XXIII, Tarragona 43005, Spain.
  • 2 CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • 3 Rovira i Virgili University, Reus 43201, Spain.
  • 4 Plataformes de Bioinformàtica i de Suport Estadístic, Institut de Recerca Biomèdica Catalunya Sud-CERCA, Tarragona 43005, Spain.
  • 5 Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela 15782, Spain.
  • 6 CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • 7 Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
  • 8 Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona 08028, Spain.
  • 9 Metabolism and Cell Signaling Laboratory, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
  • 10 Institut de Recerca Sant Pau, Barcelona 08041, Spain.
  • 11 Universitat Rovira i Virgili, Department of Electronic Engineering. Institut de Recerca Biomèdica Catalunya Sud, Tarragona 43007, Spain.
  • 12 Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain.
  • 13 Liver Vascular Biology, IDIBAPS Biomedical Research Institute, Barcelona 08036, Spain.
  • 14 Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.
PMID: 42284407 DOI: 10.1126/sciadv.aec8873
Abstract

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.

Figures
Products