Control Of Mitochondrial Structure And Antioxidant Response By The Atpase Inhibitory Factor 1 Define A Novel Potential Oncogenic Mechanism

The ATPase inhibitory factor 1 (IF1) is an ubiquitously expressed mitochondrial protein that blocks the reversal of the F1Fo-ATPsynthase, preventing dissipation of cellular ATP and ischaemic damage. Many human cancers express high levels of IF1, which suppress cell death and enhance tumour cell invasion and chemoresistance. In this study, we assessed the effect of IF1 over-expression on mitochondrial redox balance and apoptotic cristae remodelling. We found that IF1 maintains ATP levels under apoptosis and reduces glutathione (GSH) loss and inactivation of peroxiredoxin 3 (Prx3). This correlates with inhibition of the metallopeptidase OMA1-mediated processing of the pro-fusion dynamin related protein optic atrophy 1 (OPA1), impeding cristae remodelling and apoptosis completion. IF1 therefore has a pivotal antioxidant activity that hinders the OMA1/OPA1-dependent deconstruction of mitochondrial morphology and cellular demise. The data presented here highlight a dual regulatory activity of IF1 on both mitochondrial bioenergetics and structure, resulting in increased proliferative capacity of tumour cells and significantly contributing to the molecular signalling of mitochondria in cancer.