The Pro-Oncogenic Protein IF<sub>1</sub> Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation
Cancer cells overexpress IF<sub>1</sub>, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (Δμ<sub>H</sub><sup>+</sup>) falls, as in ischemia. Other roles have been ascribed to IF<sub>1</sub...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/19/14624 |
| Summary: | Cancer cells overexpress IF<sub>1</sub>, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (Δμ<sub>H</sub><sup>+</sup>) falls, as in ischemia. Other roles have been ascribed to IF<sub>1</sub>, but the associated molecular mechanisms are still under debate. We investigated the ability of IF<sub>1</sub> 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<sub>1</sub>-silenced and parental cells were exposed to the FCCP uncoupler to collapse Δμ<sub>H</sub><sup>+</sup> and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF<sub>1</sub>-expressing and IF<sub>1</sub>-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF<sub>1</sub>-expressing cells only. Interestingly, the presence of IF<sub>1</sub> 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<sub>1</sub>, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF<sub>1</sub> may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production. |
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| ISSN: | 1661-6596 1422-0067 |