Mitochondrial autophagy and injury in the liver in α 1-antitrypsin deficiency

Jeffrey H. Teckman, Jae Koo An, Keith Blomenkamp, Bela Schmidt, David Perlmutter

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185 Scopus citations


Homozygous, PIZZ α1-antitrypsin (α1-AT) deficiency is associated with chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of mutant α 1-anti-trypsin Z (α1-ATZ) 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 α 1-ATZ 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 α1-ATZ also involves the mitochondria, with specific patterns of both mitochondrial autophagy and mitochondrial injury seen in cell culture models of α1-AT deficiency, in PiZ transgenic mouse liver, and in liver from α 1-AT-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 α1-AT deficiency and suggest the possibility of mechanism-based therapeutic interventions.

Original languageEnglish
Pages (from-to)G851-G862
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number5 49-5
StatePublished - May 2004


  • Autophagy
  • Cyclosporin A
  • Mitochondria
  • Quality control
  • α-antitrypsin


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