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1 Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, Saint Louis, MO, USA
2 Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
3 Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
* To whom correspondence should be addressed. E-mail: teckman{at}pcfnotes1.wustl.edu.
Homozygous, PIZZ alpha-1-antitrypsin (
1AT) deficiency is associated with
chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of
mutant 1ATZ protein retained in the endoplasmic reticulum (ER) of hepatocytes.
However, the exact mechanism(s) by which retention of this aggregated mutant protein
leads to cellular injury are still unknown. Previous studies have shown that retention of
mutant 1ATZ in the ER induces an intense autophagic response in hepatocytes. In this
study we present evidence that the autophagic response induced by ER retention of
1ATZ also involves the mitochondria, with specific patterns of both mitochondrial
autophagy and mitochondrial injury seen in cell culture models of 1AT deficiency, in
PiZ transgenic mouse liver, and in liver from 1AT deficient patients. Evidence for a
unique pattern of caspase activation was also detected. Administration of cyclosporin A,
an inhibitor of mitochondrial permeability transition, to PiZ mice was associated with a
reduction in mitochondrial autophagy and injury and reduced mortality during
experimental stress. These results provide evidence for the novel concept that
mitochondrial damage and caspase activation play a role in the mechanism of liver cell
injury in 1AT deficiency and suggest the possibility of mechanism-based therapeutic
interventions.
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