PROJECT SUMMARY: α1-antitrypsin deficiency (ATD) liver disease is one of the most common genetic causes of liver disease in children and adults. The only currently available treatment is liver transplantation. The pathobiology of the liver disease begins with a point mutation in α1-antitrypsin (AT), one of the most abundant secretory glycoproteins of the liver. The variant, α1-antitrypsin Z (ATZ), is prone to misfolding and that leads to its accumulation within the early part of the secretory pathway of liver cells. Most of the ATZ accumulates in the endoplasmic reticulum (ER) as polymers and aggregates, and we now know that it is this accumulation of polymerogenic, aggregation-prone ATZ that initiates the process of liver damage by a gain-of-toxic function mechanism. Very little is known about the pathobiological steps after accumulation of ATZ that result in liver damage but it is assumed that liver cell function becomes impaired with stereotypical fibrogenic consequences. Marked alterations of mitochondria have been observed in liver cells of human ATD patients and the PiZ mouse model of ATD, leading to speculation that mitochondrial dysfunction is at least part of the final steps in the demise of liver cell function that characterizes severe ATD liver disease. Over the years we have learned that only a sub-group of homozygotes for ATZ develop progressive liver disease and the majority completely escape clinical effects. This observation has led to the recognition that genetic and environmental modifiers play an important role in the pathobiological effects of ATZ. Work led by the Perlmutter laboratory has shown that the intracellular degradation pathway known as autophagy is a key determinant of ATZ accumulation in liver cells and that drugs which enhance the autophagic degradation of ATZ decrease hepatic fibrosis in animal models, including the ATZ nematode and PiZ mouse models. Other recent studies have shown specificity for the molecular pathways involved in autophagy of specific organelles, and the term `ER-phagy' has recently been recognized as at least part of the process by which ATZ is specifically degraded. Furthermore, a very important new study has shown that at least one ER-phagy pathway is regulated by oxidative phosphorylation genes and mitochondrial function. Based on these considerations and new preliminary data described in the proposal, we now believe that mitochondrial impairment is a key part of the pathobiology of ATD liver disease in two ways, impaired liver cell energy metabolism and reduced autophagic response, and, therein, that mitochondrial function is a very appealing target for potential therapeutic interventions. In this grant we propose to investigate the effects of ATZ accumulation on mitochondrial function to better understand the mechanism by which liver is damaged and to investigate whether mitochondrial function can be targeted for therapy. Our overarching goal with these studies is to provide a basis f...