Role of iron overload and ferroptosis in heart disease

Abstract

The essential trace element iron is a key component of hemoglobin, playing a role in erythropoiesis and oxygen transport. In addition, iron plays a key role in several enzymatic and metabolic processes. Iron deficiency causes anemia, whereas iron overload causes organ-related diseases such as heart failure, liver cirrhosis, and diabetes mellitus. Therefore, maintaining iron homeostasis is essential for the survival of nearly all living organisms. Iron overload-related cardiomyopathy is a secondary form of heart disease resulting from iron accumulation in the myocardium and is the leading cause of morbidity in hereditary hemochromatosis, thalassemia major, and other conditions associated with secondary iron overload. A growing body of epidemiological and molecular evidence supports the notion that iron overload is pathogenic and that iron chelation therapy can be clinically beneficial in treating many forms of heart disease. However, the precise mechanisms by which iron overload leads to heart disease are poorly understood. In recent years, significant progress has been made toward understanding the regulatory mechanisms that underlie iron overload in many diseases. In particular, ferroptosis, a newly identified iron-dependent form of cell death, has drawn considerable attention. Ferroptosis has morphological, biochemical, and genetic features that are distinct from other forms of cell death such as apoptosis, necrosis, and autophagy, and mounting evidence suggests that ferroptosis participates in the initiation and progression of many diseases and conditions, including tumorigenesis, ischemia/reperfusion injury, kidney failure, and diseases affecting the nervous system and the hematological system. Although the death of terminally differentiated cardiomyocytes is a crucial pathogenic factor in the development of cardiomyopathy, the underlying mechanism remains unknown. Recently, we reported that inhibiting ferroptosis in mice can protect against both chemotherapy-induced cardiomyopathy and ischemia/reperfusion-induced cardiomyopathy. With respect to the underlying mechanism, we found that excess accumulation of free iron in the mitochondria of cardiomyocytes causes membrane lipid peroxidation, providing new insights into the pathogenic mechanisms that underlie iron overload-associated cardiomyopathy. In this review, we briefly introduce the molecular mechanisms that regulate cardiac iron homeostasis. In addition, we provide an overview of studies regarding the role that iron overload-associated cardiomyopathy and ferroptosis play in the pathogenesis and progression of heart disease. Finally, we discuss the role of targeting ferroptosis as a promising new therapeutic strategy for myocardial chemotherapeutic and ischemia/reperfusion injury.