Reduction in mitochondrial iron alleviates cardiac damage during injury

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.

Getting to the “Heart” of Cardiac Disease by Decreasing Mitochondrial Iron

“…However, iron supplementation in any chronic disease with iron deficiency will likely lead to symptom improvement. Nevertheless, a subset of these patients may still have underlying myocardial iron overload, as suggested by previous reports, 7, 8 and their cardiac function may continue to deteriorate despite temporary improvement in functional capacities. Therefore, unless trials include patient outcomes and analysis of cardiac function, the use of subjective surrogate endpoints will not determine whether iron modulation therapies are actually beneficial in patients with HF.…”

“…7 We recently demonstrated that mitochondrial iron increases during cardiac ischemia/reperfusion (I/R) injury, and that modulating baseline mitochondrial iron (i.e., without underlying iron overload) is sufficient to prevent I/R injury. 8 Furthermore, both human and animal studies have provided evidence for cardiomyocyte mitochondrial iron accumulation in HF. Increased mitochondrial iron has been observed in mice with myocardial infarction- or hypertrophy-induced HF, 7 and in dog models of HF.…”

“…7 Even if iron levels are not increased in the heart of patients with HF, a reduction in baseline iron may reduce cellular oxidative stress and damage. 8 Thus, a number of human clinical studies have investigated the use of iron chelators as treatment for CVD. Infusion of an iron chelator during and after coronary artery bypass surgery is associated with improved cardiac function, and iron chelation has been shown to improve cardiac outcomes in other iron overload diseases such as thalassemia and hemochromatosis.…”

“…13 Additionally, even baseline myocardial iron levels play an important role in determining the extent of tissue injury when the heart is under stress. 8 Without first confirming the safety of iron supplementation in a study of longer duration, its wide use should not be advocated in HF patients.…”

“…This lack of protective effect of DFO against cardiac I/R was attributed to its inability to penetrate the cell and to target mitochondrial iron. 8 There are a few iron chelators that have better mitochondrial penetrance and have demonstrated protective effects in preclinical studies. 8 Further optimization of these chelators could generate novel clinical therapies for the management of cardiac diseases.…”