The Down‐Regulation of Frataxin Compromises Nrf2 Signalling and Redox Homeostasis to Promote Cardiac Remodelling

Abstract

Oxidative stress is a key contributor to the neurodegeneration in Friedreich’s ataxia (FA). While studies in neuronal models of FA have reported a diminished antioxidant response, redox homeostasis has not been examined in the FA heart, which develops a fatal cardiomyopathy. Using the MCK conditional frataxin knockout (KO) mouse, which closely mimics the development of cardiomyopathy in FA, I examined the effects of the loss of Fxn on redox homeostasis in the heart and the contribution of oxidative stress towards the development of cardiomyopathy. The main findings of this study were that down-regulation of Fxn compromises redox homeostasis in the heart as evidenced by the loss of ARE binding and increased protein modifications by oxygen free radicals. The primary cause of this shift in redox balance was attenuation of the antioxidant response due to the loss of Nrf2 expression. The mechanisms driving Nrf2 loss are multifaceted, with increased Keap1 mediated degradation and enhanced nuclear export identified in the heart. This led to the down-regulation of Nrf2 target genes in frataxin-deficient heart. A second equally prominent mechanism of Nrf2 degradation occurs in the nucleus and encompasses increased export. The alteration in turnover of nuclear Nrf2 was driven by increased activation of GSK3. Pharmacological inhibition of GSK3 activity was used to distinguish the relative contribution of these two pathways to the overall phenotype of Nrf2 down-regulation. Treatment of Fxn-deficient cardiomyoblasts revealed Keap1 mediated degradation was the primary driver of Nrf2 loss and oxidative stress. Collectively, this study identified molecular mechanisms driving Nrf2 down-regulation in FA cardiomyopathy, which may be amenable to therapeutic development.