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ToxSci Advance Access originally published online on August 8, 2006
Toxicological Sciences 2006 94(1):217-225; 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

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

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

* Liver Research Institute, University of Arizona, College of Medicine, Tucson, Arizona 85724; and {dagger} Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina 27599

Received April 18, 2006; accepted August 4, 2006

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 kb), 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 20mM 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.

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


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[Abstract] [Full Text] [PDF]


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