Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress

Lina Du, Xiaopeng Zhang, Yong Y. Han, Nancy A. Burke, Patrick M. Kochanek, Simon C. Watkins, Steven H. Graham, Joseph A. Carcillo, Csaba Szabó, Robert S.B. Clark

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    267 Scopus citations

    Abstract

    Poly(ADP-ribosylation), primarily via poly(ADP-ribose) polymerase-1 (PARP-1), is a pluripotent cellular process important for maintenance of genomic integrity and RNA transcription in cells. However, during conditions of oxidative stress and energy depletion, poly(ADP-ribosylation) paradoxically contributes to mitochondrial failure and cell death. Although it has been presumed that poly(ADP-ribosylation) within the nucleus mediates this pathologic process, PARP-1 and other poly(ADP-ribosyltransferases) are also localized within mitochondria. To this end, the presence of PARP-1 and poly(ADP-ribosylation) were verified within mitochondrial fractions from primary cortical neurons and fibroblasts. Inhibition of poly(ADP-ribosylation) within the mitochondrial compartment preserved transmembrane potential (Δψm), NAD+ content, and cellular respiration, prevented release of apoptosis-inducing factor, and reduced neuronal cell death triggered by oxidative stress. Treatment with liposomal NAD+ also preserved Δψm and cellular respiration during oxidative stress. Furthermore, inhibition of poly(ADP-ribosylation) prevented intranuclear localization of apoptosis-inducing factor and protected neurons from excitotoxic injury; and PARP-1 null fibroblasts were protected from oxidative stress-induced cell death. Collectively these data suggest that poly(ADP-ribosylation) compartmentalized to the mitochondria can be converted from a homeostatic process to a mechanism of cell death when oxidative stress is accompanied by energy depletion. These data implicate intra-mitochondrial poly(ADP-ribosylation) as an important therapeutic target for central nervous system and other diseases associated with oxidative stress and energy failure.

    Original languageEnglish (US)
    Pages (from-to)18426-18433
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume278
    Issue number20
    DOIs
    StatePublished - May 16 2003

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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    Du, L., Zhang, X., Han, Y. Y., Burke, N. A., Kochanek, P. M., Watkins, S. C., Graham, S. H., Carcillo, J. A., Szabó, C., & Clark, R. S. B. (2003). Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. Journal of Biological Chemistry, 278(20), 18426-18433. https://doi.org/10.1074/jbc.M301295200