ArticleInternational journal of molecular sciences2021
The Mechanism of Mitochondrial Injury in Alpha-1 Antitrypsin Deficiency Mediated Liver Disease.
Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Polymeric alpha-1 antitrypsin perturbs Paneth cell proteostasis and exacerbates intestinal inflammation.Signal transduction and targeted therapy · 2026Article
- Fuelling repair: metabolic regulation of alveolar type 2 cell fate in lung regeneration and disease.Disease models & mechanisms · 2026Review
- Polymerized Z-α-1 antitrypsin leads to lung injury in a murine model of emphysema.JCI insight · 2026Article
- Pioglitazone reduces hepatic α-1 antitrypsin accumulation through autophagy and AMPK activation in α-1 antitrypsin-deficient mice.American journal of physiology. Gastrointestinal and liver physiology · 2025Article
- α‑1 Antitrypsin is a potential target of inflammation and immunomodulation (Review).Molecular medicine reports · 2025Review
- Plasma Extracellular Vesicle-derived MicroRNA Associated with Human Alpha-1 Antitrypsin Deficiency-mediated Liver Disease.Journal of clinical and translational hepatology · 2025Article
- An Inducible Neural Stem Progenitor Cell Model for Testing Therapeutic Interventions Against Neurodegeneration FENIB.Drug development research · 2025Article
- Alpha-1 antitrypsin deficiency and Pi*Z allele as important co-factors in the development of liver fibrosis.World journal of hepatology · 2024Article
- Sirtuin3 promotes the degradation of hepatic Z alpha-1 antitrypsin through lipophagy.Hepatology communications · 2024Article
- Upregulated pexophagy limits the capacity of selective autophagy.Nature communications · 2024Article
- Fatty liver disease that is neither metabolic nor alcoholic.Human pathology · 2023Article
- Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin.International journal of molecular sciences · 2023Article
- NAFLD and AATD Are Two Diseases with Unbalanced Lipid Metabolism: Similarities and Differences.Biomedicines · 2023Review
- Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish.International journal of molecular sciences · 2023Article
- Fibrosis-Related Gene Profiling in Liver Biopsies of PiZZ α1-Antitrypsin Children with Different Clinical Courses.International journal of molecular sciences · 2023Article
- The unfolded protein response to PI*Z alpha-1 antitrypsin in human hepatocellular and murine models.Hepatology communications · 2022Article
- Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB.Cellular and molecular life sciences : CMLS · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.