The role of frataxin in doxorubicin-mediated cardiac hypertrophy

Abstract

(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

Short-term exercise training attenuates acute doxorubicin cardiotoxicity

“…These changes included DOXinduced increases in wall thicknesses and decreases in ventricular chamber sizes during diastole. Others have shown that DOX-induced pathologic hypertrophy can occur at the organ level as well as the cellular level [25,29]. Changes in wall thicknesses following DOX treatment are the result of a number of factors that can include cellular apoptosis, compensatory cellular hypertrophy, formation of fibrotic tissue within the chamber wall, and altered filament overlap.…”

Keeping heart homeostasis in check through the balance of iron metabolism

“…It is involved in Fe‐S cluster biogenesis and possibly in other processes related to iron metabolism . Fe‐S clusters are incorporated as important functional prosthetic groups in many enzymes involved in cellular respiration and iron metabolism . The deficiency of Fe‐S clusters caused by loss of frataxin increases the activity of IRP2 which then induces increased iron import .…”

“…Fe‐S clusters are incorporated as important functional prosthetic groups in many enzymes involved in cellular respiration and iron metabolism . The deficiency of Fe‐S clusters caused by loss of frataxin increases the activity of IRP2 which then induces increased iron import . The increase in iron import towards mitochondria and defective utilization of iron in mitochondria creates a vicious cycle of mitochondrial iron overload (MIO) which can damage this organelle via oxidative stress .…”

“…Although the exact role of frataxin in cardiac iron homeostasis remains to be elucidated, data show that recuperation of frataxin activity is directly related to correction of the Fe‐S cluster deficiency and its consequences in mitochondrial metabolism . Furthermore, recuperation of frataxin activity alleviates MIO and restores cardiac function …”

“…In line with these results are observations that iron chelation and ferroptosis inhibitors reduce DOX toxicity by protecting mitochondrial functionality. Also, the relationship between the severity of DOX toxicity and the activity of different mitochondrial iron proteins shows how important is mitochondrial iron dysregulation in DOX‐induced cardiotoxicity . Finally, the only FDA‐approved iron chelator used for DOX‐induced cardiac toxicity named dexrazoxane has been shown to be more efficacious than other iron chelators, because of its beneficial effects on mitochondrial iron dysmetabolism (Table ) .…”