The Mechanism of Mitochondrial Injury in Alpha-1 Antitrypsin Deficiency Mediated Liver Disease

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.

Alpha-1 Antitrypsin Deficiency and Risk of Lung Cancer in Never-Smokers: A Multicentre Case-Control Study

Background Lung cancer (LC) is the most commonly diagnosed cancer and the leading cause of cancer-related death in both sexes worldwide. Although its principal risk factor is smoking habit, there are genetic mutations, such as alpha-1 antitrypsin deficiency (AATD), that have been related with increased risk This study is the continuation of an earlier one published by the same group in 2015, aimed at analysing risk of LC in never-smokers, associated with carriers of the AATD genotype. Methods A multicentre case-control study was conducted in Spain across the period January 2011 to August 2019. Cases were patients with LC, and controls were patients, all never-smokers, undergoing major non-cancer-related surgery. Data were collected on epidemiological characteristics, exposure to environmental tobacco smoke (ETS), residential radon levels, and alpha-1 antitrypsin (AAT) genotype. Results The study included 457 cases (42%) and 631 controls (58%), with a predominance of women. The most frequent histological type was adenocarcinoma (77.5%), followed by squamous cell carcinoma (7.7%). No association of risk of LC was found with the status of AATD genotype carrier, both overall and broken down by age, sex, or exposure to ETS. Conclusions No risk association was found between being a carrier of an AAT deficiency genotype and LC among never-smokers. Even so, new studies are required to provide fuller information in this regard with respect to never-smokers, and possibly even include previous respiratory diseases.

Protein Misfolding and Aggregation: The Relatedness between Parkinson’s Disease and Hepatic Endoplasmic Reticulum Storage Disorders

Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson’s disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.

The Emerging Role of Proteases in Alpha-1 Antitrypsin Deficiency and Beyond

Alpha-1 Antitrypsin Deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis, or a combination of phenotypes) has not been proposed or studied. Of the 3 Neutrophil Serine Proteases (NSPs), Neutrophil Elastase (NE) was historically believed to be the sole contributor to disease pathology in AATD. Recently, Proteinase-3 (PR3) has been increasingly studied as an equal, if not greater, contributor to the disease process. Cathepsin G (CG), however, has not been extensively evaluated in this area. Matrix metalloproteinases (MMPs) have also been mentioned in the pathogenesis of AATD but have not been widely explored. This article considers the available evidence for differential protease activity in patients with AATD, including the contribution to distinct phenotypes of the disease. Due to limited literature in this area, extrapolations from studies of other chronic lung diseases with similar phenotypes, including chronic obstructive pulmonary disease (COPD) and bronchiectasis have been made. We consider a new framework of understanding defined by protease driven endotypes of disease which may lead to new opportunities for precision medicine.