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 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 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.
Overview
- The study explores how mitochondria in glioblastoma (GBM) cells adapt to and resist ionizing radiation (IR), a component of the standard treatment for GBM.
- The researchers used several approaches to investigate how mitochondrial dynamics and physiology adapt to radiation stress.
- The primary objective of the study is to uncover how mitochondria in GBM cells contribute to treatment resistance and to identify potential targets for more effective therapeutics.
Comparative Analysis & Findings
- The study demonstrates that increased fission in response to IR leads to the removal of mtDNA damage and more efficient oxygen consumption through altered ETC activities in intact mitochondria.
- Fis1, a pro-fission protein, plays a novel role in regulating the stress response through mitochondrial DNA (mtDNA) maintenance and altered mitochondrial bioenergetics.
- The data show that Fis1 targets damaged mtDNA for degradation and regulates mitochondrial bioenergetics through altered dynamics.
Implications and Future Directions
- The study's findings have significant implications for the development of more effective treatments for GBM, as they suggest that targeting mitochondrial dynamics and physiology could be a key strategy.
- Future research could focus on identifying other proteins or pathways that regulate mitochondrial dynamics and physiology in response to IR, potentially leading to new therapeutic targets.
- Understanding the molecular mechanisms underlying the regulation of mitochondrial dynamics and physiology in GBM cells could provide important insights for the design of more effective and targeted therapies.