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.
Highlights
Mitochondria play key roles in cell metabolism and bioenergetics, mediate intracellular signaling by calcium and reactive oxygen species (ROS) and regulate the execution of cell-death [1]
We demonstrate in vivo that the expression of an active mutant of human IF1 (hIF1) in hepatocytes partially inhibits oxidative phosphorylation (OXPHOS)
A hIF1-limited activity of OXPHOS in the liver predisposes to cancer progression. It appears that an enhanced cancer progression in hIF1expressing mice is related to its pro-oncogenic activity that favors an increased proliferation and an increased resistance to execute apoptosis by the hepatocarcinomas
Summary
Mitochondria play key roles in cell metabolism and bioenergetics, mediate intracellular signaling by calcium and reactive oxygen species (ROS) and regulate the execution of cell-death [1]. Most of the ATP that is required to maintain cellular activities is synthesized by the mitochondrial H+-ATP synthase [2]. Down-regulation of oxidative phosphorylation (OXPHOS) and the concurrent activation of aerobic glycolysis is a hallmark of proliferating cancer cells [1, 3] whereas an increase in oxidative metabolism halts cellular proliferation and tumor progression [1, 4, 5]. The activity of OXPHOS is required for the execution of cell death [1, 6] and in particular, the ATP synthase is needed for the execution of apoptosis [7] as recently demonstrated in neurons in vivo www.impactjournals.com/oncotarget [8]. Inhibition of the ATP synthase is involved in lifespan extension [12, 13] illustrating the relevance of this protein complex in aging and age-related diseases
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