Mitochondria are the cellular organs that generate energy using oxygen. Glioblastoma (GBM) is aggressive cancer without a cure. Due to their rapid proliferation, GBM cells need to adapt to a low oxygen environment. They do so by altering normal mitochondrial functions. One adaptation is an increased concentration of proton outside the inner mitochondrial membrane, referred to as high membrane potential, which has been shown to be critical for tumor growth. Therefore, reducing mitochondrial membrane potential may be a promising novel approach to treat GBM. However, it is unclear how GBM maintains a higher than normal mitochondrial membrane potential which normally is generated by concentratin...
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Mitochondria are the cellular organs that generate energy using oxygen. Glioblastoma (GBM) is aggressive cancer without a cure. Due to their rapid proliferation, GBM cells need to adapt to a low oxygen environment. They do so by altering normal mitochondrial functions. One adaptation is an increased concentration of proton outside the inner mitochondrial membrane, referred to as high membrane potential, which has been shown to be critical for tumor growth. Therefore, reducing mitochondrial membrane potential may be a promising novel approach to treat GBM. However, it is unclear how GBM maintains a higher than normal mitochondrial membrane potential which normally is generated by concentrating proton outside the mitochondrial inner membrane in an oxygen dependent process called oxidation respiration. GBM has low oxidation respiration yet has a high membrane potential. The mechanism underlying this phenomenon is unclear. In this project, we propose to prove that an abnormal protein process referred to as msiCTE causes addition of selective amino acid (aa)-tails to ATP5a, which composes a protein channel that allows proton to cross the inner membrane and thereby plays a key role in maintaining membrane potential. These aa-tails tend to aggregate and impair normal function. Our results show that in GBM, ATP5a has significant accumulations of aa-tails, which are not found in normal neural stem cells. We hypothesize that the aa-tails block the ATP5a channel that will increase mitochondrial potential and facilitate tumor proliferation. We identified a small molecule inhibitor that can prevent aa-tail formation. Treating GBM cells with this inhibitor effectively prevents tumor growth without affecting normal neural stem cells. We will test this inhibitor in a mouse model of GBM. Successful completion of this study will not only provide an explanation of how GBM cells maintain a higher than normal mitochondrial potential, but also provide a new potential treatment of GBM.
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