Abstract 2384: Investigating Fis1 upregulation as a stress response in glioblastoma cells

Abstract Dysfunctional mitochondrial dynamics contribute to many pathologies, and elevated levels of mitochondrial fission have been observed in glioblastoma (GBM). Mitochondrial fission 1 protein (Fis1) plays a minor role in basal fission, but has been shown to be more critical for pathological fission. Further, it has been shown to facilitate peripheral fission events, generally occurring after cellular exposure to stress, as a means to prepare damaged mitochondria for degradation through mitophagy. Therefore, my goal is to elucidate the role of Fis1, an integral outer membrane partner protein, in mitochondrial fission within GBM cells. I propose that Fis1 plays a protective role against therapeutic treatment in GBM. This is demonstrated through experiments showing that ionizing radiation (IR) leads to upregulation of Fis1 protein levels, while GBM cell viability is simultaneously unaffected. Further, this increase in Fis1 results in an increase in mitochondrial fission, which likely reflects an increase in mitophagy as a response to IR stress. Thus, I anticipate that GBM cells upregulate Fis1 as a protective measure and that targeting Fis1 function could have therapeutic benefit. In this regard, I have found that depletion of Fis1 alters mitochondrial morphology, and I am studying changes in mitochondrial bioenergetics to correlate ultrastructural changes with mitochondrial function. Preliminary data suggests that Fis1 knockdown in Gli36 cells leads to decreased oxidative phosphorylation and ATP production, with deficits observed specifically in Complex I and III. Concurrently, I am assessing potential synergistic effects of combined radiation and Fis1 inhibition on GBM cell viability and proliferation. To do this, I will use genetic and small molecule approaches to inhibit Fis1-dependent mitochondrial fission. Overall, these studies will demonstrate whether Fis1 drives pathological fission to promote cancer cell growth and proliferation. Additionally, the selective inhibition will evaluate Fis1 as a novel therapeutic target in GBM. Citation Format: Yuli Buckley, Adina Brett-Morris, Maria Stoll, Jason Mears. Investigating Fis1 upregulation as a stress response in glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2384.