Abstract 15100: A Decrease in Mitochondrial, but Not Cytosolic, Iron Protects Against Cardiac Ischemia-Reperfusion Damage Through a Reduction in ROS

Abstract

Introduction: Iron can catalyze the formation of reactive oxygen species (ROS) and promote tissue damage. While some studies suggested benefits with iron chelation therapy in ischemic heart disease (IHD), several others failed to show any benefits. Mitochondria are a major site of iron utilization and ROS production, and mitochondrial iron accumulation has been associated with increased oxidative stress. We therefore hypothesized that mitochondrial iron plays a causative role in ischemia/reperfusion (I/R) damage, and a decrease in mitochondrial iron (as opposed to cytoplasmic iron) would be sufficient to protect against I/R injury. Results: We observed an increase in cardiac mitochondrial iron in mice after I/R injury. Using two iron chelators with distinct mitochondrial permeability, i.e., 2,2’-bipyridyl (BPD, a mitochondria-accessible iron chelator) and deferoxamine (DFO, an iron chelator that does not modulate mitochondrial iron), we demonstrated that mice pretreated with BPD but not DFO were protected against I/R injury. Similar results were obtained in vitro . Since these two iron chelators also modulate iron in other subcellular compartments, we used transgenic (TG) mice with cardiomyocyte-specific overexpression of the mitochondrial iron export protein ATP-binding cassette (ABC)-B8 to confirm that modulation of mitochondrial iron alone is sufficient to confer protection. ABCB8 TG mice had significantly lower mitochondrial iron (but normal cytosolic iron) in the heart compared to nontransgenic (NTG) littermates at baseline, but exhibited normal cardiac function. After I/R, ABCB8 TG mice displayed significantly less apoptosis and lower levels of markers of ROS and better preserved cardiac function than NTG littermates, suggesting that a reduction in mitochondrial iron protects against I/R injury, most likely through a reduction in ROS. Conclusions: Our findings demonstrate that selective reduction in mitochondrial iron is sufficient to protect against I/R injury. Thus, targeting mitochondrial iron with selective iron chelators may provide a novel approach for the treatment of IHD.