Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Research Abstract Details 

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Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Abstract Text:

Mary Lynn Bajt,Cathleen Cover,John J Lemasters,Hartmut Jaeschke,

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.

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Publishing Authors By Initials

ML Bajt,C Cover,JJ Lemasters,H Jaeschke,

For similar proteins: mitochondrial proteins research abstracts see: proteins: mitochondrial proteins research

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Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Toxicological sciences : an official journal of th

VOLUME: 94

Page Numbers: 217-25

Journal Abbreviation: Toxicol. Sci.

ISSN: 1096-6080

DAY: 8

MONTH: 08

YEAR: 2006

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9805461

Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Keywords Mesh Terms:

KEYWORDS: Mitochondrial Proteins

MESH TERMS: metabolism

Chemical & Substance for Abstract: Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Information

Substance Name: endonuclease G

Registry Number: EC 3.1.21.-

Grant and Affiliation Information for Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury.

AFFILIATION: Liver Research Institute, University of Arizona, College of Medicine, Tucson, Arizona 85724, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: R01 DK70195

ACRONYM: DK

MEDLINETA: Toxicol Sci

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