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ToxSci Advance Access published online on August 8, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl077
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received April 18, 2006
Accepted August 4, 2006

Systems Toxicology

Nuclear Translocation of Endonuclease G and Apoptosis-Inducing Factor During Acetaminophen-Induced Liver Cell Injury

Mary Lynn Bajt 1, Cathleen Cover 1, John J. Lemasters 2, and Hartmut Jaeschke 1 *

1 Liver Research Institute, University of Arizona, College of Medicine, Tucson, AZ 85724
2 Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599

* To whom correspondence should be addressed.
Hartmut Jaeschke, E-mail: jaeschke{at}email.arizona.edu


  Abstract

Mitochondrial dysfunction and internucleosomal DNA fragmentation are well-recognized features of acetaminophen (AAP)-induced hepatocyte cell death. However, the endonucleases responsible for this effect have not been identified. Apoptosis-inducing factor (AIF) and endonuclease G are nucleases located in the intermembrane space of mitochondria. AIF is thought to trigger chromatin condensation and induce cleavage of DNA into high molecular weight fragments (50-300 kilobases) and endonuclease G can produce oligonucleosomal DNA fragments. Therefore, the objective of this investigation was to test the hypothesis that endonuclease G and AIF could be involved in AAP-induced nuclear DNA fragmentation. Using immunofluorescence microscopy, it was shown that in primary cultured mouse hepatocytes endonuclease G and AIF translocated to the nucleus between 3 and 6 h after exposure to 5 mM AAP. In contrast, other mitochondrial intermembrane proteins such as cytochrome c or the second mitochondria-derived activator of caspases (Smac) did not accumulate in the nucleus. The translocation of AIF and endonuclease G correlated with mitochondrial dysfunction as indicated by the progressive loss of the mitochondrial membrane potential (measured with the JC-1 assay), and the appearance of nuclear DNA fragments in the cytosol (determined by an anti-histone ELISA). Pretreatment with 20 mM N-acetylcysteine prevented mitochondrial dysfunction, the nuclear translocation of endonuclease G and AIF, and the nuclear DNA fragmentation. The data support the conclusion that endonuclease G and AIF translocate to the nucleus in response to AAP-induced mitochondrial dysfunction and may be responsible, at least in part, for the initial DNA fragmentation during AAP hepatotoxicity.

Keywords: acetaminophen hepatotoxicity; endonucleases; N-acetylcysteine; cultured hepatocytes; DNA fragmentation.
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