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Jimena_Ruiz_Dissertation
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Dissertation
INVESTIGATING MITOCHONDRIAL STRESS RESPONSE ON DIET-INDUCED GERM CELL FERROPTOSIS IN CAENORHABDITIS ELEGANS
Doctor of Philosophy (PhD), Washington State University
2026
Abstract
Mitochondrial dysfunction is a key contributor to a wide range of human diseases, including neurodegenerative, metabolic, and mitochondrial disorders. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has also been implicated in many of these pathologies. However, the relationship between mitochondrial stress and ferroptosis remains incompletely understood. The work presented in this dissertation aims to examine the role of mitochondrial stress response in DGLA-induced ferroptosis using the model organism Caenorhabditis elegans. Previous work from our laboratory demonstrated that the dietary ω-6 PUFA, DGLA, induces germ cell death and sterility through ferroptosis in C. elegans. Building on this model, we investigated how mitochondrial function influences susceptibility to DGLA-induced ferroptosis. We found that mitochondrial dysfunction does not uniformly sensitize organisms to ferroptosis. Instead, genetic perturbations of the electron transport chain often reduced DGLA-induced sterility, suggesting that mitochondrial stress can activateprotective pathways. We identified activation of the mitochondrial unfolded protein response (mitoUPR), mediated by the transcription factor ATFS-1, as a key contributor to this protection. Constitutive activation of ATFS-1 significantly reduced ferroptosis, while loss of ATFS-1 had minimal effect. Further analysis revealed that mitochondrial stress alters lipid metabolism and transport, including upregulation of vitellogenin genes, suggesting that redistribution or sequestration of PUFAs may limit lipid peroxidation and ferroptotic damage. In addition, we examined C. elegans models carrying patient-relevant mitochondrial disease mutations susceptibility to ferroptosis, which we found to be influenced by the severity of mitochondrial dysfunction, supporting a threshold-dependent model of disease. Together, these findings establish C. elegans as a powerful system for studying ferroptosis in vivo and reveal that mitochondrial stress responses, rather than mitochondrial dysfunction alone, are key determinants of ferroptotic susceptibility.
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Details
- Title
- INVESTIGATING MITOCHONDRIAL STRESS RESPONSE ON DIET-INDUCED GERM CELL FERROPTOSIS IN CAENORHABDITIS ELEGANS
- Creators
- Jimena Ruiz
- Contributors
- Jennifer L Watts (Advisor)Heather Koehler (Committee Member)James MacLean (Committee Member)Ryan Driskell (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 165
- Identifiers
- 99901393898401842
- Language
- English
- Resource Type
- Dissertation