Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction

Marlene F. Sisemore, Jiang Zheng, Joy C. Yang, David A. Thompson, Charles Plopper, Gino A Cortopassi, Bruce D. Hammock

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Leukotoxin, a cytochrome P450-derived epoxide of linoleic acid, has been implicated as a causative factor in acute respiratory distress syndrome. Conversion of this fatty acid epoxide to leukotoxin diol by epoxide hydrolase has been hypothesized as the critical activation step in leukotoxin-induced cellular toxicity. In both human and insect cells, we observed that leukotoxin diol causes acute cellular toxicity and that cyclosporin A, an inhibitor of the mitochondrial permeability transition, ameliorates leukotoxin diol-associated toxicity. To evaluate mitochondria as a target of leukotoxin diol, multiple aspects of mitochondrial integrity were evaluated in both cell- and organelle-based assays. Leukotoxin diol specifically activated the mitochondrial permeability transition, resulting in release of cytochrome c and subsequent cell death. Pretreatment with cyclosporin A inhibited these effects and, furthermore, limited in vivo toxicity. While the mechanisms underlying leukotoxin-mediated toxicity remain to be fully elucidated, the observation that leukotoxin diol disrupts mitochondrial function specifically through activation of the mitochondrial permeability transition suggests at least one mechanism through which leukotoxin diol may exert its activity in physiological contexts.

Original languageEnglish (US)
Pages (from-to)32-37
Number of pages6
JournalArchives of Biochemistry and Biophysics
Volume392
Issue number1
DOIs
StatePublished - Aug 1 2001

Fingerprint

Toxicity
Permeability
Epoxy Compounds
Cyclosporine
Chemical activation
Epoxide Hydrolases
Mitochondria
Adult Respiratory Distress Syndrome
Cell death
Linoleic Acid
Cytochromes c
9,10-dihydroxy-12-octadecenoic acid
Organelles
Cytochrome P-450 Enzyme System
Insects
Assays
Cell Death
Fatty Acids
leukotoxin

Keywords

  • Ards
  • Cyclosporin
  • Epome
  • Epoxide
  • Epoxyoctadecamonoenoic
  • Hydrolase
  • Leukotoxin
  • Mitochondria

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction. / Sisemore, Marlene F.; Zheng, Jiang; Yang, Joy C.; Thompson, David A.; Plopper, Charles; Cortopassi, Gino A; Hammock, Bruce D.

In: Archives of Biochemistry and Biophysics, Vol. 392, No. 1, 01.08.2001, p. 32-37.

Research output: Contribution to journalArticle

Sisemore, Marlene F. ; Zheng, Jiang ; Yang, Joy C. ; Thompson, David A. ; Plopper, Charles ; Cortopassi, Gino A ; Hammock, Bruce D. / Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction. In: Archives of Biochemistry and Biophysics. 2001 ; Vol. 392, No. 1. pp. 32-37.
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