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Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state

2015; Impact Journals LLC; Volume: 7; Issue: 1 Linguagem: Inglês

10.18632/oncotarget.6357

1949-2553

Fulvio Santacatterina, Laura Sánchez-Cenizo, Laura Formentini, Maysa A. Mobasher, Estela Casas, Carlos B. Rueda, Inmaculada Martínez‐Reyes, Cristina Núñez de Arenas, Javier García‐Bermúdez, Juan M. Zapata, María Sánchez‐Aragó, Jorgina Satrústegui, Ángela M. Valverde, José M. Cuezva,

Mitochondrial Function and Pathology

// Fulvio Santacatterina 1,2,3,* , Laura Sánchez-Cenizo 1,2,3,* , Laura Formentini 1,2,3,* , Maysa A. Mobasher 4,5 , Estela Casas 1,2,3 , Carlos B. Rueda 1,2,6 , Inmaculada Martínez-Reyes 1,2,3 , Cristina Núñez de Arenas 1,2 , Javier García-Bermúdez 1,2,3 , Juan M. Zapata 4 , María Sánchez-Aragó 1,2,3 , Jorgina Satrústegui 1,2,6 , Ángela M. Valverde 4,5 and José M. Cuezva 1,2,3 1 Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain 3 Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain 4 Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain 5 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain 6 Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain * These authors have equally contributed to this work Correspondence to: José M. Cuezva, email: // Keywords : ATPase inhibitory factor 1, cancer, energy metabolism, mitochondria, reactive oxygen species Received : June 30, 2015 Accepted : November 14, 2015 Published : November 22, 2015 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.