Dokument: Implication of carbon monoxide signaling in cellular stress response
| Titel: | Implication of carbon monoxide signaling in cellular stress response | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=56028 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20210427-102407-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Stucki, David [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Stahl, Wilhelm [Gutachter] Prof. Urlacher, Vlada [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | All organisms are exposed to potentially hazardous noxae, including xenobiotics, natural compounds, toxins, drugs, or heavy metals, challenging the organism on the cellular level. For cytoprotection, different stress response pathways have evolved to counteract various noxae and enable survival of the organism. The Nrf2/Keap1 system orchestrates cellular defense against electrophilic compounds, including prooxidative and alkylating agents. Upon activation of the Nrf2/Keap1 system, gene expression of enzymes related to antioxidant defense or phase II xenobiotic metabolism for elimination of electrophilic alkylating agents, is induced. Furthermore, heme oxygenase-1 (HO-1) is typically highly upregulated upon Nrf2/Keap1 activation. HO-1 catalyzes the degradation of heme to biliverdin, iron and carbon monoxide (CO). CO is a small gaseous signaling molecule and HO-1 is therefore thought to play a keyrole in stress-induced CO signaling.
Here, the implication of CO signaling in cellular stress response was investigated. A selection of suitable tools, CO releasing molecules (CORMs), for the study of CO signaling was performed first, leading to the use of CORM-401 as appropriate model compound for intracellular CO delivery. Biological effects determined upon exposure of cells to CORM-401 were also found after endogenous CO production by heme oxygenases and provision of substrate (heme). It was shown, that the initial CO signal modulates mitochondrial respiratory chain activity, further triggering two different signaling pathways. One implicated the formation of ROS and a subsequent metabolic rewiring from glycolysis to pentose phosphate pathway for NADPH regeneration, which is needed for antioxidant defense. The other pathway comprised the inhibition of mitochondrial ATP production, leading to elevated AMP levels and activation of AMP-activated protein kinase (AMPK) signaling. AMPK likely activated the target kinase ULK1, which is an inducer of mitophagy. Since AMPK activity is also known to induce mitochondrial biogenesis, a regulatory role of CO signaling on preservation of mitochondrial function upon exogenous stress is suggested to be mediated by this pathway. It was further shown, that CO delivered by CORM-401 modulates the activity of cytochrome P450-dependent monooxygenases (CYPs) in HepG2 cells. This finding may hint to a putative feedback inhibition of electrophilic stress, since CYPs can form electrophiles from xenobiotics (bioactivation). It also demonstrates the interconnection of CO signaling with other stress response pathways (xenobiotic metabolism). | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Biochemie und Molekularbiologie I | |||||||
| Dokument erstellt am: | 27.04.2021 | |||||||
| Dateien geändert am: | 27.04.2021 | |||||||
| Promotionsantrag am: | 08.09.2020 | |||||||
| Datum der Promotion: | 23.03.2021 |
