Dokument: Role of apolipoprotein MIC26 in mitochondrial and metabolic disorders
| Titel: | Role of apolipoprotein MIC26 in mitochondrial and metabolic disorders | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=66145 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240617-110719-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Lubeck, Melissa [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Reichert, Andreas [Gutachter] Prof. Dr. Al-Hasani, Hadi [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Abnormal functioning and regulation of the human metabolism is implicated in the onset of
severe life hampering diseases including type 2 diabetes or non-alcoholic fatty liver disease. Mitochondria are pivotal for essential metabolic functions including cellular lipid metabolism, energy generation and fuel utilization. Malfunctioning mitochondria result in disease development and progression. As the primary metabolic hub mitochondria utilize the majority of cellular nutrients and orchestrate their conversion or storage in form of energy. Moreover, mitochondrial dysfunction has a prominent role in obesity and insulin resistance. Mitochondrial ultrastructure and intra- as well as intermitochondrial dynamics are essential features for proper mitochondrial functionality. Mitochondrial ultrastructure, especially in terms of cristae formation, maintenance, and dynamics, are dependent on the MICOS complex, comprising seven mammalian subunits: MIC60, MIC10, MIC13, MIC19, MIC25, MIC27 and MIC26. MIC26, hypothesized to have a dual cellular localization within the mitochondrial MICOS complex and the cellular secretory pathway, has been implicated to play a role in diabetes and lipid metabolism. This dissertation aimed to elucidate the cellular localization, function of MIC26 and its contribution to metabolic diseases. Using multiple biochemical assays, cell and tissue models, including MIC26 KO cell lines, MIC26 overexpression, along with immunoblot analysis and mass spectrometry, we demonstrate that MIC26 is exclusively present as a 22 kDa protein in the mitochondria. Additionally, we showed that MIC26 plays an essential physiological role. Patients, harboring a MIC26E178X mutation, inducing protein truncation, developed progeria-like phenotypes, resulting in lethality. Biological evaluation unveiled mitochondrial ultrastructure defects, abnormalities in mitochondrial dynamics and protein instability. To elucidate the functional role of MIC26 regulating cellular metabolism under nutritional overload conditions, a multi-omics study supported by validation using various assays in wildtype and MIC26 KO cells under normo- and hyperglycemia, was conducted. We identified MIC26 to be a crucial cellular regulator of mitochondrial metabolite usage. MIC26 exerts a suppressive influence on glycolysis, cholesterol, and lipid metabolism under normoglycemic conditions, with opposing effects under hyperglycemia. Deleting MIC26 resulted in nutritional independent rewiring of cellular glutamine usage and oxidative phosphorylation. Overall, we identified MIC26 as a metabolic rheostat, maintaining mitochondrial ultrastructure, leading to stability of several mitochondrial metabolite transporters while it directly impacts lipid and cholesterol metabolism by harboring a lipid binding domain, resulting in alterations of lipid metabolism. We hypothesize that balanced MIC26 levels and functionality are required to prevent excess fat accumulation under normal nutrient conditions and to mediate energy storage under nutrient overload. Thus, we propose MIC26 to be essential to prevent obesity and the development of metabolic diseases. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 17.06.2024 | |||||||
| Dateien geändert am: | 17.06.2024 | |||||||
| Promotionsantrag am: | 07.03.2024 | |||||||
| Datum der Promotion: | 15.05.2024 |
