Reactive γ-ketoaldehydes formed via the isoprostane pathway disrupt mitochondrial respiration and calcium homeostasis

Irina G. Stavrovskaya, Sergei V. Baranov, Xiaofeng Guo, Sean S. Davies, L. Jackson Roberts, Bruce S. Kristal

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Isoketals (IsoKs) are γ-ketoaldehydes formed via the isoprostane pathway of arachidonic acid peroxidation and are among the most reactive by-products of lipid peroxidation. IsoKs selectively adduct to protein lysine residues and are highly cytotoxic, but the targets and molecular events involved in IsoK-induced cell death are poorly defined. Our previous work established that physiologically relevant aldehydes induce mitochondrial dysfunction (Kristal et al., J. Biol. Chem. 271:6033-6038; 1996). We therefore examined whether IsoKs induced mitochondrial dysfunction. Incubation of mitochondria with synthetic IsoKs in the presence or absence of Ca2+ was associated with alterations in mitochondrial respiration, membrane potential (δψ), and pyridine nucleotide redox state. IsoKs dose dependently (0.5-4μM) accelerated liver mitochondria swelling induced by low concentrations of Ca2+ and Zn2+ or by the prooxidant tert-butylhydroperoxide, and release of cytochrome c, with similar observations in heart/brain mitochondria. The mitochondrial permeability transition (mPT) inhibitor cyclosporine A delayed IsoK-induced mitochondria dysfunction. The actions of IsoKs are consistent with interactions with cytochrome c, a protein rich in lysine residues. Direct reaction of IsoKs with select lysines in cytochrome c was demonstrated using high-resolution mass spectrometry. Overall, these results suggest that IsoKs may, in part, mediate their cytotoxic effects through induction of the mPT and subsequent activation of downstream cell death cascades.

Original languageEnglish (US)
Pages (from-to)567-579
Number of pages13
JournalFree Radical Biology and Medicine
Volume49
Issue number4
DOIs
StatePublished - Aug 1 2010

Keywords

  • High-resolution mass spectrometry
  • Lipid peroxidation
  • Mitochondrial permeability transition
  • Oxidative modification of cytochrome c
  • Oxidative stress
  • γ-Ketoaldehydes

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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