Journal
JOURNAL OF NEUROCHEMISTRY
Volume 104, Issue 6, Pages 1700-1711Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1471-4159.2007.05114.x
Keywords
ADP-ribosyltransferase; controlled cortical impact; electron transport chain; poly(ADP-ribose) polymerase; poly(ADP-ribose) synthetase; proteomics
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Funding
- NICHD NIH HHS [R01 HD045968, T32 HD40686] Funding Source: Medline
- NIGMS NIH HHS [GM060915] Funding Source: Medline
- NINDS NIH HHS [R01 NS38620, P50 NS30318] Funding Source: Medline
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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.
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