title: Reactive gamma-ketoaldehydes formed via the isoprostane pathway disrupt mitochondrial respiration and calcium homeostasis.
abstract: Isoketals (IsoKs) are gamma-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 Ca(2+) was associated with alterations in mitochondrial respiration, membrane potential (DeltaPsi), and pyridine nucleotide redox state. IsoKs dose dependently (0.5-4microM) accelerated liver mitochondria swelling induced by low concentrations of Ca(2+) and Zn(2+) 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.
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, 221 Longwood Avenue, Room LM322, Boston, MA 02115, USA.
authors.forename: Irina G
authors.initials: IG
authors.lastname: Stavrovskaya
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Baranov
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Guo
authors.forename: Sean S
authors.initials: SS
authors.lastname: Davies
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D019069:Cell Respiration; D006706:Homeostasis; D028421:Isoprostanes / Q000737:chemistry / Q000378:metabolism*; D015227:Lipid Peroxidation; D008930:Mitochondria, Liver / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D028421:Isoprostanes; D002118:Calcium
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