Mitochondrial dynamic modulators attenuate iron overload-mediated cardiac toxicity via decreased mitochondrial fission, mitophagy/autophagy, and apoptosis in iron-overloaded rats

Abstract

One of the leading causes of death for individuals with iron overload is iron overload cardiomyopathy (IOC). Iron overload causes cardiac mitochondrial dysfunction, which ultimately results in heart failure and death. The potential mechanism of iron overload-induced mitochondrial dysfunction involves the disequilibrium between cardiac mitochondrial fission and fusion. Nevertheless, the information regarding cardiac mitochondrial dynamics under iron overload conditions remains limited. The roles of mitochondrial dynamics were identified in IOC. To induce iron overload, male Wistar rats were injected with iron dextran for four weeks. Then, while continuing iron dextran injection, four groups of iron-overloaded rats were given injections of either vehicle, mitochondrial fusion promoter (M1), mitochondrial division inhibitor 1 (Mdivi-1), or iron chelator deferoxamine (DFO) for two weeks. In the non-iron loaded (control) group, rats received vehicles without iron dextran injection. Cardiac function, mitochondrial function, mitochondrial dynamics, mitophagy/autophagy, and apoptosis were assessed at the end of treatment. The increased expression of mitochondrial fission-, mitophagy/autophagy-, and apoptosis-related proteins were correlated with impaired mitochondrial and cardiac functions in iron-overloaded rats. Interestingly, both mitochondrial dynamics modulators reduced cardiac mitochondrial fission, mitophagy/autophagy, and apoptosis, as well as restored cardiac function to be comparable to those treated with iron chelator DFO. Our findings indicated that the imbalance of mitochondrial dynamics is a potential mechanism responsible for cardiomyocyte death induced by IOC, and this could be a novel target for interventions for IOC via either the promotion of mitochondrial fusion or the inhibition of mitochondrial fission.