The role of frataxin in doxorubicin‐mediated cardiac hypertrophy (648.6)

Abstract

Heart failure is the major fatal adverse effect associated with cancer chemotherapeutic, doxorubicin (DOX). We and others have found that the progression towards DOX mediated heart failure involves myocardial energy dysregulation and the development of cardiac hypertrophy. Hypothesis: We hypothesize that Frataxin (FXN) is a key player in the development and progression of DOX mediated cardiac hypertrophy. Results: Recently, we observed that DOX (2µM) treatment in H9C2 cardiomyocytes results in the reduction of the active version of the mitochondrial protein FXN which is a major player in the iron sulfur cluster biogenesis. This deficiency in the active form of FXN resulted in an increase in mitochondrial iron accumulation and consequent reduction in activities of aconitase and the electron transferring complexes in mitochondria thus greatly affecting oxidative phosphorylation leading to reduced measured levels of ATP. Further the increase in mitochondrial iron accumulation lead to an increase in production of mitochondrial reactive oxygen species (ROS) and oxidative stress and helps further explain the subsequent cardiac hypertrophy. In order to verify that restoration of FXN could prevent against myocardial energy dysregulation and cardiac hypertrophy, we created FXN over expressing and knock out cell lines and found that over expression promoted iron homeostasis in the mitochondria which lead to a significant improvement in oxidative phosphorylation, substantial decrease in ROS production in the mitochondria and protected against the development of DOX mediated cardiac hypertrophy. Conclusion: Over expression of FXN in the mitochondria is protective against DOX mediated myocardial energy dysregulation and subsequent cardiac hypertrophy.Grant Funding Source: Auburn university Internal grant program