The Pro-Oncogenic Protein IF₁ Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation.

ABSTRACT: Cancer cells overexpress IF₁, 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 IF₁, but the associated molecular mechanisms are still under debate. We investigated the ability of IF₁ 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. IF₁-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 IF₁-expressing and IF₁-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF₁-expressing cells only. Interestingly, the presence of IF₁ 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 IF₁, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF₁ may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production.

SUBMITTER: Righetti R 

PROVIDER: S-EPMC10572598 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature