Abstract
Excess cellular iron increases reactive oxygen species (ROS) production and causes cellular damage. Mitochondria are the major site of iron metabolism and ROS production; however, few studies have investigated the role of mitochondrial iron in the development of cardiac disorders, such as ischemic heart disease or cardiomyopathy (CM). We observe increased mitochondrial iron in mice after ischemia/reperfusion (I/R) and in human hearts with ischemic CM, and hypothesize that decreasing mitochondrial iron protects against I/R damage and the development of CM. Reducing mitochondrial iron genetically through cardiac-specific overexpression of a mitochondrial iron export protein or pharmacologically using a mitochondria-permeable iron chelator protects mice against I/R injury. Furthermore, decreasing mitochondrial iron protects the murine hearts in a model of spontaneous CM with mitochondrial iron accumulation. Reduced mitochondrial ROS that is independent of alterations in the electron transport chain's ROS producing capacity contributes to the protective effects. Overall, our findings suggest that mitochondrial iron contributes to cardiac ischemic damage, and may be a novel therapeutic target against ischemic heart disease.
Highlights
Cardiovascular disease accounts for nearly six hundred thousand deaths per year in United States (Heron, 2013) and over 4 million deaths in Europe (Nichols et al, 2012), making it the most common cause of death in the Western World
Since labile iron can catalyze the formation of reactive oxygen species (ROS), which in turn further increases free iron, we measured chelatable mitochondrial and cytoplasmic iron in H9c2 cardiomyoblasts exposed to H2O2, a model designed to simulate the surge of ROS during the reperfusion stage of I/R
Based on our observation that mitochondrial iron is significantly increased in mice after I/R, in cells treated with H2O2, and in human patients with ischemic cardiomyopathy (ISCM), we hypothesized that a specific reduction in mitochondrial iron would offer protection against cardiac injury
Summary
Cardiovascular disease accounts for nearly six hundred thousand deaths per year in United States (Heron, 2013) and over 4 million deaths in Europe (Nichols et al, 2012), making it the most common cause of death in the Western World. It is believed that the extent of cardiac tissue damage is correlated with the development of heart failure (Foo et al, 2005; McAlindon et al, 2015); no clinically available therapy directly targets cardiomyocytes in order to reduce damage after ischemia/reperfusion (I/R) injury. The development of novel therapies targeting cardiomyocyte death is essential. Excess iron can cause tissue damage through the production of reactive oxygen species (ROS) via the Fenton-like and Harbor–Weiss reactions (Aigner et al, 2008). Previous studies have demonstrated a role for lysosomal iron in radiation-mediated or H2O2-induced cell death (Yu et al, 2003; Persson et al, 2005; Kurz et al, 2010). While one study suggested that extracellular iron is involved in renal I/R injury (de Vries et al, 2004), very few studies have discerned the contribution of baseline iron in various subcellular compartments to I/R injury in cells and animals
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