Mitochondrial Physiology Network 10.9: 98 (2005) - download pdf

Reversible redox dependent modulation of mitochondrial aconitase and proteolytic activity status during cardiac ischemia reperfusion.

Anne-Laure Bulteau¹, L Szweda LI^2, B Friguet

¹Universite Paris7-Denis Diderot, Paris, France and ²Oklahoma Research Foundation, Omaha, USA. - anne-laure.bulteau@paris7.jussieu.fr

    Aconitase, a citric acid cycle enzyme that converts citrate to isocitrate, belongs to the family of iron-sulfur containing dehydratases whose activities depend on the redox state of the cubane [4Fe-4S] cluster. Recent evidence indicates that mitochondrial aconitase can be reversibly inhibited or progress to irreversible inactivation and degradation in response to pro-oxidants [1]. Cardiac ischemia/reperfusion is associated with an increase in mitochondrial free radical production. In the current study, the effects of reperfusion-induced production of pro-oxidants on mitochondrial aconitase and proteolytic activity both in cytoplasm and mitochondria 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 in the mitochondria increases during early reperfusion followed by a time-dependent reduction in activity to control levels. These alterations in proteolytic activity parallel an increase and subsequent decrease in the level of oxidatively modified protein. However, proteasome activity is decreased upon the same times of reperfusion. Aconitase activity exhibited a marked decline in activity followed by reactivation during cardiac reperfusion.  Loss and regain in activity involves reversible sulfhydryl modification.  Aconitase was found to associate with the iron binding protein frataxin exclusively during reperfusion.  In vitro frataxin has been shown to act as a chaperone protein that protects aconitase from [4Fe-4S]²⁺ cluster disassembly, irreversible inactivation, and potentially degradation [2].  Thus, the response of mitochondrial aconitase and ATP-dependent proteolytic activity to reperfusion-induced pro-oxidant production appears to be a regulated event that would be expected to reduce irreparable damage to the mitochondria.

1.  Bulteau AL, Ikeda-Saito M, Szweda LI (2003) Redox-dependent modulation of aconitase activity in intact mitochondria.  Biochemistry 42: 14846-14855.

2.  Bulteau AL, O Neill H, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI (2004) A novel role of frataxin as an iron protein required for pro-oxidant induced modulation of mitochondrial activity. Science 305: 129-292.