Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway

Loss-of-function variants in the ferredoxin reductase (FDXR) gene result in a primary mitochondrial disease in humans, involving abnormal mitochondrial iron accumulation. However, the molecular mechanism is not fully understood. To better understand the underlying pathology of FDXR-related disease, we generated a mouse model corresponding to the hotspot variant found in humans. We demonstrated increased lipid peroxidation in the inner mitochondrial and plasma membranes, resulting in susceptibility to ferroptosis. Closer examination revealed that disruption of the NRF2 pathway and its target gene SLC7A11 appear to play important roles in this pathogenic process. Finally, administration of the NRF2 activator omaveloxolone, which was recently approved by the FDA for treatment of Friedreich's ataxia, helps mitigate the pathogenesis. Together, our results suggest that ferroptosis is a novel underlying mechanism of FDXR-related disease and that activation of NRF2 could be an immediate, viable treatment option for individuals with FDXR-related disease and other conditions involving aberrant iron metabolism.