Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite

Xiaopeng Zhang, Jun Chen, Steven H. Graham, Lina Du, Patrick M. Kochanek, Romesh Draviam, Fengli Guo, Paula D. Nathaniel, Csaba Szabó, Simon C. Watkins, Robert S.B. Clark

    Research output: Contribution to journalArticle

    213 Scopus citations

    Abstract

    Programmed cell death occurs after ischemic, excitotoxic, and traumatic brain injury (TBI). Recently, a caspase-independent pathway involving intranuclear translocation of mitochondrial apoptosis-inducing factor (AIF) has been reported in vitro; but whether this occurs after acute brain injury was unknown. To address this question adult rats were sacrificed at various times after TBI. Western blot analysis on subcellular protein fractions demonstrated intranuclear localization of AIF in ipsilateral cortex and hippocampus at 2-72 h. Immunocyto-chemical analysis showed AIF labeling in neuronal nuclei with DNA fragmentation in the ipsilateral cortex and hippocampus. Immunoelectronmicroscopy verified intranuclear localization of AIF in hippocampal neurons after TBI, primarily in regions of euchromatin. Large-scale DNA fragmentation (∼50 kbp), a signature event in AIF-mediated cell death, was detected in ipsilateral cortex and hippocampi by 6 h. Neuron-enriched cultures exposed to peroxynitrite also demonstrated intranuclear AIF and large-scale DNA fragmentation concurrent with impaired mitochondrial respiration and cell death, events that are inhibited by treatment with a peroxynitrite decomposition catalyst. Intranuclear localization of AIF and large-scale DNA fragmentation occurs after TBI and in neurons under conditions of oxidative/nitrosative stress, providing the first evidence of this alternative mechanism by which programmed cell death may proceed in neurons after brain injury.

    Original languageEnglish (US)
    Pages (from-to)181-191
    Number of pages11
    JournalJournal of neurochemistry
    Volume82
    Issue number1
    DOIs
    StatePublished - 2002

    Keywords

    • Apoptosis
    • Brain injury
    • Controlled cortical impact
    • DNA damage
    • Programmed cell death

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

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    Zhang, X., Chen, J., Graham, S. H., Du, L., Kochanek, P. M., Draviam, R., Guo, F., Nathaniel, P. D., Szabó, C., Watkins, S. C., & Clark, R. S. B. (2002). Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite. Journal of neurochemistry, 82(1), 181-191. https://doi.org/10.1046/j.1471-4159.2002.00975.x