ABSTRACT
In response to external stress, mitochondrial dynamics is often disrupted, but the associated physiologic changes are often uncharacterized. In many cancers, including glioblastoma (GBM), mitochondrial dysfunction has been observed. Understanding how mitochondrial dynamics and physiology contribute to treatment resistance will lead to more targeted and effective therapeutics. This study aims to uncover how mitochondria in GBM cells adapt to and resist ionizing radiation (IR), a component of the standard of care for GBM. Using several approaches, we investigated how mitochondrial dynamics and physiology adapt to radiation stress, and we uncover a novel role for Fis1, a pro-fission protein, in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics. Importantly, our data demonstrate that increased fission in response to IR leads to removal of mtDNA damage and more efficient oxygen consumption through altered electron transport chain (ETC) activities in intact mitochondria. These findings demonstrate a key role for Fis1 in targeting damaged mtDNA for degradation and regulating mitochondrial bioenergetics through altered dynamics.
Footnotes
Author contributions
Conceptualization: Y.B., J.A.M.; Funding acquisition: J.A.M.; Investigation: Y.B., M.S.K.S., J.A.M.; Project administration: J.A.M.; Resources: C.L.H., J.A.M.; Supervision: C.L.H., J.A.M.; Validation: Y.B.; Writing – original draft: Y.B.; Writing – review & editing: Y.B., C.H., J.A.M.
Funding
This research was supported by funding from the National Institutes of Health (T32 GM008803 to Y.B.; R01 CA208516 and R01 GM125844 to J.A.M.). Deposited in PMC for release after 12 months.
Data availability
All relevant data can be found within the article and its supplementary information.
Special Issue
This article is part of the Special Issue ‘Cell Biology of Mitochondria’, guest edited by Ana J. Garcia-Saez and Heidi McBride. See related articles at https://journals.biologists.com/jcs/issue/138/9.
