title: Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state.
abstract: The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Off mice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the relevance of mitochondrial activity in hepatocarcinogenesis. The expression of hIF1 promotes the inhibition of OXPHOS in both Tet-On and Tet-Off mouse models and induces a state of metabolic preconditioning guided by the activation of the stress kinases AMPK and p38 MAPK. Expression of the transgene significantly augmented proliferation and apoptotic resistance of carcinoma cells, which contributed to an enhanced diethylnitrosamine-induced liver carcinogenesis. Moreover, the expression of hIF1 also diminished acetaminophen-induced apoptosis, which is unrelated to differences in permeability transition pore opening. Mechanistically, cell survival in hIF1-preconditioned hepatocytes results from a nuclear factor-erythroid 2-related factor (Nrf2)-guided antioxidant response. The results emphasize in vivo that a metabolic phenotype with a restrained OXPHOS in the liver is prone to the development of cancer.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Santacatterina
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Sánchez-Cenizo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Formentini
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Maysa A
authors.initials: MA
authors.lastname: Mobasher
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Casas
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Rueda
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Martínez-Reyes
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Núñez de Arenas
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Bermúdez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Zapata
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Sánchez-Aragó
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Cuezva
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010085:Oxidative Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
chemical_list: D055372:AMP-Activated Protein Kinases; D000082:Acetaminophen; D011506:Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000097795:ATPase Inhibitory Protein
keywords: ATPase inhibitory factor 1; cancer; energy metabolism; mitochondria; reactive oxygen species