Dokument: Physiological and Pharmacological Regulation of Ferroptosis
| Titel: | Physiological and Pharmacological Regulation of Ferroptosis | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=70858 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250930-113223-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Thewes, Leonie Christin [Autor] | |||||||
| Dateien: |
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| Beitragende: | PD Dr. Berndt, Carsten [Gutachter] Prof. Dr. Bauer, Petra [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Ferroptosis is a non-apoptotic, iron-dependent cell death mechanism that relies on the accumulation of lipid peroxides. While several aspects of ferroptosis have been described
in recent years, physiologically relevant molecular mechanisms modulating ferroptosis are still poorly understood. This study identifies a novel redox-dependent mechanism that regulates ferroptosis through posttranslational modification of glutathione peroxidase 4 (GPX4), a central enzyme in the suppression of ferroptosis. It is shown that glutathionylation at cysteine 75 of GPX4 impairs its ability to bind to cell membranes, thereby inhibiting its lipid peroxide-reducing activity and making cells more susceptible to ferroptotic cell death. Furthermore, the obtained data show that glutaredoxin 2 (Grx2), a key player in redox regulation, can reverse this glutathionylation, thereby restoring GPX4's membrane association and ability to reduce lipid peroxidation. This redox-dependent regulation by Grx2 represents one of the first described physiological mechanisms that directly modulates ferroptosis sensitivity. To investigate this mechanism, a combination of cellular, tissue-based and biochemical models have been used, in particular cells and tissues from transgenic mice as well as proteins isolated from these. Beyond the mechanistic insight, the relevance of drug-dependent regulation of ferroptosis in disease context was investigated. Ferroptosis is associated with inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA) and osteoarthritis (OA), in which oxidative stress and lipid peroxidation contribute to disease progression. Although previous data from our research group has been shown that the MS drug diroximel fumarate protects oligodendroglia cells and MS patients against ferroptosis, this work shows that it has no protective effect on cells derived from RA and OA patients. For this part of the study, human cells and tissues from OA and RA patients were used. In summary, this work uncovers a previously unknown, physiologically relevant mechanism of ferroptosis regulation by Grx2-mediated control of GPX4 activity and highlights the importance of cell-specific responses in the development of ferroptosis therapies. Key techniques included cell survival assays and lipid peroxidation detection by flow cytometry, as well as western blot, immunohistochemistry, and qPCR to analyze protein and mRNA expression. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 30.09.2025 | |||||||
| Dateien geändert am: | 30.09.2025 | |||||||
| Promotionsantrag am: | 06.05.2025 | |||||||
| Datum der Promotion: | 12.09.2025 |
