316 - Paradoxical disruption of Nrf2 signaling despite mitochondrial iron driven oxidative stress in Friedreich’s ataxia cardiomyopathy

Abstract

Listen

Translate article

Cardiomyopathy is the leading cause of mortality for the most prevalent inherited ataxia, Friedreich’s ataxia (FA). Deficient expression of the mitochondrial protein frataxin that is crucial for mitochondrial iron metabolism is the cause of FA, which exhibits marked mitochondrial Fe accumulation. Our studies using a conditional cardiac frataxin knockout (KO) mouse that mirrors FA cardiomyopathy have shown frataxin deletion leads to pronounced trafficking of cardiac iron from the cytosol to the mitochondrion, leading to a cytosolic iron-deficiency and mitochondrial iron accumulation in the form of non-protein-bound, biomineral iron aggregates. The ensuing oxidative stress is likely a key contributor to FA pathology. The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is the master regulator of cellular antioxidant response. In the frataxin KO mouse, our studies demonstrated increased protein and GSH oxidation in the KO relative to wild-type (WT) littermates. Despite this, we found paradoxical decreases in total and nuclear Nrf2 protein and an increase in its inhibitor, Keap1, which mediates Nrf2 degradation in the cytosol. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via Gsk3β-signaling was found in the KO heart. This is evident by: (i) increased Gsk3β activation; (ii) increased Fyn-mediated nuclear Nrf2 export; and (iii) increased expression of β-TrCP that is involved in Nrf2 degradation. Furthermore, a corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA was observed in KO heart. Collectively, despite marked mitochondrial iron accumulation in FA cardiomyopathy, Nrf2 activity was disrupt via two mechanisms: increased Keap1 that decreases cytosolic Nrf2, and the activation of Gsk3β-signaling that decreases nuclear Nrf2.