Ischemic preconditioning targets the respiration of synaptic mitochondria via protein kinase Cε

Kunjan R Dave, R. Anthony DeFazio, Ami Raval, Alessandra Torraco, Isabel Saul, Antonio Barrientos, Miguel Perez-Pinzon

Research output: Contribution to journalArticle

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Abstract

In the brain, ischemic preconditioning (IPC) diminishes mitochondrial dysfunction after ischemia and confers neuroprotection. Activation of ε protein kinase C (εPKC) has been proposed to be a key neuroprotective pathway during IPC. We tested the hypothesis that IPC increases the levels of εPKC in synaptosomes from rat hippocampus, resulting in improved synaptic mitochondrial respiration. Preconditioning significantly increased the level of hippocampal synaptosomal εPKC to 152% of sham-operated animals at 2 d of reperfusion, the time of peak neuroprotection. We tested the effect of εPKC activation on hippocampal synaptic mitochondrial respiration 2 d after preconditioning. Treatment with the specific εPKC activating peptide, tat-ψεRACK (tat-ψε-receptor for activated C kinase), increased the rate of oxygen consumption in the presence of substrates for complexes I, II, and IV to 157, 153, and 131% of control (tat peptide alone). In parallel, we found that εPKC activation in synaptosomes from preconditioned animals resulted in altered levels of phosphorylated mitochondrial respiratory chain proteins: increased serine and tyrosine phosphorylation of 18 kDa subunit of complex I, decreased serine phosphorylation of FeS protein in complex III, increased threonine phosphorylation of COX IV (cytochrome oxidase IV), increased mitochondrial membrane potential, and decreased H2O2 production. In brief, ischemic preconditioning promoted significant increases in the level of synaptosomal εPKC. Activation of εPKC increased synaptosomal mitochondrial respiration and phosphorylation of mitochondrial respiratory chain proteins. We propose that, at 48 h of reperfusion after ischemic preconditioning, εPKC is poised at synaptic mitochondria to respond to ischemia either by direct phosphorylation or activation of the εPKC signaling pathway.

Original languageEnglish
Pages (from-to)4172-4182
Number of pages11
JournalJournal of Neuroscience
Volume28
Issue number16
DOIs
StatePublished - Apr 16 2008

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Keywords

  • Cell death
  • Cerebral ischemia
  • Electron transport chain
  • Hippocampus
  • Neuroprotection
  • Phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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