Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury

Yichen Lai, Yaming Chen, Simon C. Watkins, Paula D. Nathaniel, Fengli Guo, Patrick M. Kochanek, Larry W. Jenkins, Csaba Szabó, Robert S.B. Clark

    Research output: Contribution to journalArticle

    86 Scopus citations

    Abstract

    Poly-ADP-ribosylation is a post-translational modification performed by poly(ADP-ribose) polymerases (PARP), involved in many diverse cellular functions including DNA repair, transcription, and long-term potentiation. Paradoxically, PARP over-activation under pathologic conditions including traumatic brain injury (TBI) results in cell death. We previously demonstrated that intra-mitochondrial poly-ADP-ribosylation occurs following excitotoxic and oxidative injury in vitro. Here we sought to identify mitochondrial proteins modified by poly-ADP-ribosylation after TBI in vivo. Poly-ADP-ribosylation within mitochondria from injured brain after experimental TBI in rats was first verified using western blot and immuno-electron microscopy. Poly-ADP-ribosylated mitochondrial proteins identified using a targeted proteomic approach included voltage-dependent anion channel-1, mitofilin, mitochondrial stress proteins, and the electron transport chain components F1F0 ATPase, cytochrome c oxidase, and cytochrome c reductase. To examine the functional consequences of mitochondrial poly-ADP-ribosylation, isolated rat brain mitochondria were exposed to conditions of nitrosative stress known to activate PARP. PARP activation-induced reductions in State 3 respiration were prevented by the PARP-1 inhibitor 5-iodo-6-amino-1,2-benzopyrone or exogenous poly(ADP-ribose) glycohydrolase. As the effects of PARP activation on mitochondrial respiration appear regulated by poly(ADP-ribose) glycohydrolase, a direct effect of poly-ADP-ribosylation on electron transport chain function is suggested. These findings may be of relevance to TBI and other diseases where mitochondrial dysfunction occurs.

    Original languageEnglish (US)
    Pages (from-to)1700-1711
    Number of pages12
    JournalJournal of neurochemistry
    Volume104
    Issue number6
    DOIs
    StatePublished - Mar 1 2008

    Keywords

    • ADP-ribosyltransferase
    • Controlled cortical impact
    • Electron transport chain
    • Poly(ADP-ribose) polymerase
    • Poly(ADP-ribose) synthetase
    • Proteomics

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

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  • Cite this

    Lai, Y., Chen, Y., Watkins, S. C., Nathaniel, P. D., Guo, F., Kochanek, P. M., Jenkins, L. W., Szabó, C., & Clark, R. S. B. (2008). Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury. Journal of neurochemistry, 104(6), 1700-1711. https://doi.org/10.1111/j.1471-4159.2007.05114.x