Figure 8: Effect of frataxin deficiency on mitochondrial dysfunction and the pathogenesis of Friedreich’s ataxia (FA). It has been well established that frataxin deficiency leads to the dysregulation of mitochondrial iron metabolism that affects the iron-sulfur cluster (ISC) and heme biosynthesis. Notably, there is the abnormal accumulation of redox active iron in the mitochondria that exacerbates ROS generation, which is further potentiated by the defect in antioxidant defense, as evident by the decrease in NFE2L2 levels and its downstream antioxidant target genes. Furthermore, studies have shown that frataxin deficiency disrupts energy metabolism due to the impairment of the mitochondrial respiratory chain. These pathological features collectively attribute to mitochondrial dysfunction in FA, which can activate autophagy and potentially induce apoptosis and mitophagy. As a result, this leads to the neurodegeneration, ataxia, and cardiomyopathy observed in FA.