Abstract 98: Reducing Mitochondrial, But Not Cytosolic Iron, Protects The Heart Against Ischemia-reperfusion Injury

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Abstract

Introduction: Iron is essential for the activity of a large number of cellular proteins, but excess free iron can cause cellular damage through production of reactive oxygen species (ROS). Mitochondria are the major site of cellular iron homeostasis, and we recently showed the mitochondrial iron export is mediated by ATP-binding cassette protein-B8 (ABCB8). The role of mitochondrial iron in ischemia-reperfusion (I/R) injury in the heart has not been examined. We hypothesize that mitochondrial iron has a critical role in I/R damage and a reduction of mitochondrial iron is protective against I/R injury through a reduction in ROS.

Results: Cardiomyocyte-specific ABCB8 transgenic (TG) mice had significantly lower mitochondrial iron in the heart than nontransgenic (NTG) littermates at baseline, but their cardiac function and the expression of key antioxidant systems were indistinguishable from NTG littermates. To study the role of mitochondrial iron in I/R injury, we subjected ABCB8 TG mice to I/R. TG mice displayed significantly less apoptosis compared to NTG littermates (11.76% vs. 17.63%, p<0.05, n=4-6) and had significantly reduced lipid peroxidation products 48 hours after I/R.

To further confirm that our in vivo finding was due to reduced mitochondrial iron, we studied the effect of pharmacological reduction of mitochondrial iron in vitro. 2,2-bipyridyl (BPD) is a mitochondria-accessible iron chelator while deferoxamine (DFO) has poor penetrance into mitochondria. Treating rat cardiomyoblasts H9C2 with BPD but not DFO significantly reduced chelatable mitochondrial iron, as measured by staining cells with rhodamine B-[(1,10-phenanthrolin-5-yl)aminocarbonyl]benzyl ester. In addition, BPD but not DFO pretreatment protected cells against H2O2 induced cell death (p<0.05). BPD treatment in mice decreased baseline mitochondrial iron and significantly preserved cardiac function after I/R.

Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is protective in I/R injury, and show that mitochondrial iron is a source of ROS and cellular damage in I/R. Thus, targeting mitochondrial iron with selective iron chelators, as studied in our system, may provide a novel approach for treatment of ischemic heart disease.

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