Investigating the Role of Energy Metabolism In the Radiation-Induced Bystander Effect
Bibliographic record
Abstract
The radiation-induced bystander effect (RIBE) refers to phenomenon where cells that are not directly exposed to radiation still exhibit biological changes that closely resemble that of radiation exposure. This effect is mediated by signaling molecules communicated from irradiated cells to nearby or distant non-irradiated (bystander) cells. The transmission of bystander signals can occur via gap junctions between adjacent cells, through the release of soluble factors or exosomes into the extracellular space, or low-level electromagnetic signals enabling communication between physically separated cells. In response to direct or indirect radiation damage, the cellular response system necessitates many energy requiring processes. ATP synthesis via glycolysis and mitochondrial oxidative phosphorylation are the main energy metabolism pathways in cells. This thesis aimed to further explore how these pathways are involved in RIBE communication. The first area examined NADH dehydrogenase, a key enzyme in the mitochondrial oxidative phosphorylation (OXPHOS) system. The second area examined glycolysis and the mitochondrial OXPHOS system using various metabolic inhibitors. The third area examined how melanin can influence the overall bystander communication process. Complex I (NADH dehydrogenase) in the mitochondrial oxidative phosphorylation system is downregulated by bystander signalling in HCT116 p53 wild type cells. The alternative NADH dehydrogenase, NDI1, enzyme from Saccharomyces cerevisiae (yeast) can bypass Complex I dysfunction due to genetic mutation or chemical inhibition, allowing for continued NADH oxidation and electron transfer in the mitochondrial electron transport chain. HCT116 p53 wild type cells were transfected with the empty vector control gene or NDI1 gene, to study how different NADH dehydrogenases can alter cell response to bystander signalling. The mitoSOX assay was used to assess mitochondrial ROS production. The clonogenic assay was used to assess long-term reproductive cell death. All three cell lines (parent cells, empty vector control transfected cells, and NDI1 transfected cells) exhibited a similar dose response following direct γ-irradiation from Cesium-137. Compared to parent and empty vector control transfected cells, NDI1 transfected cells did not exhibit the bystander effect. These preliminary results suggest NADH dehydrogenase role in ATP generation or NAD+/NADH REDOX are involved in the production of bystander effects. Glycolytic and mitochondrial energy metabolism function synergistically to meet cellular energy demands. The involvement of other metabolic enzymes in the bystander effect was assessed in human HCT116 p53 wild type and fish CHSE214 cell lines using the metabolic inhibitors 2-deoxy-D-glucose, sodium oxamate, and rotenone. Inhibitor treatment reduced or eliminated biophoton-mediated cell killing effects and reactive oxygen species (ROS) production. The clonogenic survival of treated cultures did not significantly differ from controls when a UV-filter was placed between directly irradiated and bystander cultures. It was concluded electromagnetic signals within the UV wavelengths were involved in producing the radiation-induced bystander effect and energy metabolism pathways were required for bystander cell response. The RIBE observed in fish cells was found to be comparable to that in human cells, suggesting evolutionary conservation of this effect. To further investigate how ROS are involved in the initiation of bystander communication in directly irradiated cells and bystander responses in non-irradiated cells. Skin cell lines (HaCaT and B16F10 cells) with differing endogenous melanin levels were paired in a mix-and-match experiment to see how the natural antioxidant/broadband UV absorber affects biophoton-mediated bystander communication. When put in context with previous work on melanin, these results support the role of anti-oxidants in reducing or preventing RIBE. The findings presented in this thesis contribute to our understanding of the metabolic pathways underlying the radiation-induced bystander effect, and how altering these pathways can modulate overall cell response.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".