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 Szabo, Robert S B Clark

Research output: Contribution to journalArticle

80 Citations (Scopus)

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 2008
Externally publishedYes

Fingerprint

Mitochondrial Proteins
Poly(ADP-ribose) Polymerases
Adenosine Diphosphate
Brain
Mitochondria
Electron Transport
Chemical activation
Voltage-Dependent Anion Channel 1
Respiration
Rats
Cytochrome Reductases
Mitochondrial Diseases
Immunoelectron Microscopy
Long-Term Potentiation
Electron Transport Complex IV
Protein Transport
Post Translational Protein Processing
Heat-Shock Proteins
Cytochromes c
DNA Repair

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

Cite this

Lai, Y., Chen, Y., Watkins, S. C., Nathaniel, P. D., Guo, F., Kochanek, P. M., ... 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

Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury. / Lai, Yichen; Chen, Yaming; Watkins, Simon C.; Nathaniel, Paula D.; Guo, Fengli; Kochanek, Patrick M.; Jenkins, Larry W.; Szabo, Csaba; Clark, Robert S B.

In: Journal of Neurochemistry, Vol. 104, No. 6, 03.2008, p. 1700-1711.

Research output: Contribution to journalArticle

Lai, Y, Chen, Y, Watkins, SC, Nathaniel, PD, Guo, F, Kochanek, PM, Jenkins, LW, Szabo, C & Clark, RSB 2008, 'Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury', Journal of Neurochemistry, vol. 104, no. 6, pp. 1700-1711. https://doi.org/10.1111/j.1471-4159.2007.05114.x
Lai, Yichen ; Chen, Yaming ; Watkins, Simon C. ; Nathaniel, Paula D. ; Guo, Fengli ; Kochanek, Patrick M. ; Jenkins, Larry W. ; Szabo, Csaba ; Clark, Robert S B. / Identification of poly-ADP-ribosylated mitochondrial proteins after traumatic brain injury. In: Journal of Neurochemistry. 2008 ; Vol. 104, No. 6. pp. 1700-1711.
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