Involvement of cytosolic and mitochondrial iron in iron overload cardiomyopathy: an update

Abstract

Iron overload cardiomyopathy (IOC) is a major cause of death in patients with diseases associated with chronic anemia such as thalassemia or sickle cell disease after chronic blood transfusions. Associated with iron overload conditions, there is excess free iron that enters cardiomyocytes through both L- and T-type calcium channels thereby resulting in increased reactive oxygen species being generated via Haber-Weiss and Fenton reactions. It is thought that an increase in reactive oxygen species contributes to high morbidity and mortality rates. Recent studies have, however, suggested that it is iron overload in mitochondria that contributes to cellular oxidative stress, mitochondrial damage, cardiac arrhythmias, as well as the development of cardiomyopathy. Iron chelators, antioxidants, and/or calcium channel blockers have been demonstrated to prevent and ameliorate cardiac dysfunction in animal models as well as in patients suffering from cardiac iron overload. Hence, either a mono-therapy or combination therapies with any of the aforementioned agents may serve as a novel treatment in iron-overload patients in the near future. In the present article, we review the mechanisms of cytosolic and/or mitochondrial iron load in the heart which may contribute synergistically or independently to the development of iron-associated cardiomyopathy. We also review available as well as potential future novel treatments.

Keywords: Animal models; Cytosol; Iron overload cardiomyopathy; Mitochondria; Treatment.

Figure 1. Dietary uptake, membrane import, export, and metabolism of iron in the cell and mitochondrion

See details in section 3.1. ABCB8/7: ATP-binding cassette protein B8 or 7; DMT1: divalent metal transporter1; Fe³⁺: ferric iron; Fe²⁺: ferrous iron; FPN1: Ferroportin 1; FtMt: mitochondrial ferritin; ISC: iron sulfur cluster; LIP: labile iron pool; LTCC: L-type calcium channel; Mfrn2: mitoferrin 2; mCU: mitochondrial calcium uniporter; NTBI: Non-Tf bound iron; STEAP3: Six-transmembrane epithelial antigen of the prostate 3, an endosomal reductase; Tf: Transferrin. TfR: Transferrin receptor; TTCC: T-type calcium channel

Figure 2. Iron overload-mediated oxidative stress and effects on mitochondrial and cellular function

Potential targets for treatment are indicated by the numbers 1–8 in the parentheses. LIP: labile iron pool; LTCC: L-type calcium channel; mCU: mitochondrial calcium uniporter; mPTP: mitochondrial permeability transition pore; Mfrn2: mitoferrin-2; NCX: Na-Ca Exchanger; NTBI: Non-Tf bound iron; PLN: Phospholamban; ROS: Reactive Oxygen Species; RyR: Ryanodine Receptor; SR: Sarcoplasmic Reticulum; SERCA: SR Ca²⁺ ATPase; TTCC: T-type calcium channel