Reversible redox-dependent modulation of mitochondrial aconitase and proteolytic activity during in vivo cardiac ischemia/reperfusion

Anne Laure Bulteau, Kathleen C. Lundberg, Masao Ikeda-Saito, Grazia Isaya, Luke I. Szweda

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112 Citations (Scopus)

Abstract

Prooxidents can induce reversible inhibition or irreversible inactivation and degradation of the mitochondrial enzyme aconitase. Cardiac ischemia reperfusion is associated with an increase in mitochondrial free radical production. In the current study, the effects of reperfusion-induced production of prooxidants on mitochondrial aconitase and proteolytic activity were determined to assess whether alterations represented a regulated response to changes in redox status or oxidative damage. Evidence is provided that ATP-dependent proteolytic activity increased during early reperfusion followed by a time-dependent reduction in activity to control levels. These alterations in proteolytic activity paralleled an increase and subsequent decrease in the level of oxidatively modified protein. In vitro data supports a role for prooxidants in the activation of ATP-dependent proteolytic activity. Despite inhibition during early periods of reperfusion, aconitase was not degraded under the conditions of these experiments. Aconitase activity exhibited a decline in activity followed by reactivation during cardiac reperfusion. Loss and regain in activity involved reversible sulfhydryl modification. Aconitase was found to associate with the iron binding protein frataxin exclusively during reperfusion. In vitro, frataxin has been shown to protect aconitase from [4Fe-4S] 2+ cluster disassembly, irreversible inactivation, and, potentially, degradation. Thus, the response of mitochondrial aconitase and ATP-dependent proteolytic activity to reperfusion-induced prooxidant production appears to be a regulated event that would be expected to reduce irreparable damage to the mitochondria.

Original languageEnglish
Pages (from-to)5987-5991
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number17
DOIs
Publication statusPublished - 2005 Apr 26

ASJC Scopus subject areas

  • General

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