The Mechanism of Mitochondrial Injury in Alpha-1 Antitrypsin Deficiency Mediated Liver Disease
| Autor: | Nazli Khodayari, Rejean L. Wang, Regina Oshins, Yuanqing Lu, Michael Millett, Alek M. Aranyos, Sayedamin Mostofizadeh, Yogesh Scindia, Tammy O. Flagg, Mark Brantly |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
QH301-705.5
lipid droplets Mice Transgenic Catalysis Article Cell Line Inorganic Chemistry Mice alpha-1 antitrypsin deficiency protein misfolding mitochondrial injury alpha 1-Antitrypsin Deficiency Animals Humans Physical and Theoretical Chemistry Biology (General) Molecular Biology QD1-999 Spectroscopy Sequence Analysis RNA Gene Expression Profiling Organic Chemistry General Medicine Endoplasmic Reticulum Stress Computer Science Applications Disease Models Animal Protein Transport Chemistry Gain of Function Mutation alpha 1-Antitrypsin Proteolysis Hepatocytes |
| Zdroj: | International Journal of Molecular Sciences; Volume 22; Issue 24; Pages: 13255 International Journal of Molecular Sciences, Vol 22, Iss 13255, p 13255 (2021) International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms222413255 |
| Popis: | Alpha-1 antitrypsin deficiency (AATD) is caused by a single mutation in the SERPINA1 gene, which culminates in the accumulation of misfolded alpha-1 antitrypsin (ZAAT) within the endoplasmic reticulum (ER) of hepatocytes. AATD is associated with liver disease resulting from hepatocyte injury due to ZAAT-mediated toxic gain-of-function and ER stress. There is evidence of mitochondrial damage in AATD-mediated liver disease; however, the mechanism by which hepatocyte retention of aggregated ZAAT leads to mitochondrial injury is unknown. Previous studies have shown that ER stress is associated with both high concentrations of fatty acids and mitochondrial dysfunction in hepatocytes. Using a human AAT transgenic mouse model and hepatocyte cell lines, we show abnormal mitochondrial morphology and function, and dysregulated lipid metabolism, which are associated with hepatic expression and accumulation of ZAAT. We also describe a novel mechanism of ZAAT-mediated mitochondrial dysfunction. We provide evidence that misfolded ZAAT translocates to the mitochondria for degradation. Furthermore, inhibition of ZAAT expression restores the mitochondrial function in ZAAT-expressing hepatocytes. Altogether, our results show that ZAAT aggregation in hepatocytes leads to mitochondrial dysfunction. Our findings suggest a plausible model for AATD liver injury and the possibility of mechanism-based therapeutic interventions for AATD liver disease. |
| Databáze: | OpenAIRE |
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