The Pro-Oncogenic Protein IF 1 Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation.

Cancer cells overexpress IF 1 , the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (Δμ H + ) falls, as in ischemia. Other roles have been ascribed to IF 1 , but the associated molecular mechanisms are still under debate. We investigated the ability of IF 1 to promote survival and proliferation in osteosarcoma and colon carcinoma cells exposed to conditions mimicking ischemia and reperfusion, as occurs in vivo, particularly in solid tumors. IF 1 -silenced and parental cells were exposed to the FCCP uncoupler to collapse Δμ H + and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF 1 -expressing and IF 1 -silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF 1 -expressing cells only. Interestingly, the presence of IF 1 also conferred a proliferative advantage to cells highly dependent on oxidative phosphorylation when the uncoupler was washed out, mimicking cell re-oxygenation. Overall, our results indicate that IF 1 , by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF 1 may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production.