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

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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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-Offmice 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- Offmouse 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.

Original languageEnglish (US)
Pages (from-to)490-508
Number of pages19
JournalOncotarget
Volume7
Issue number1
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • ATPase inhibitory factor 1
  • Cancer
  • Energy metabolism
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • Oncology

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