Restoration of Mitochondrial Function by Small-Molecule Iron Transporter in Friedreich’s Ataxia

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PROJECT SUMMARY/ABSTRACT Friedreich’s ataxia (FRDA) is an inherited autosomal neurodegenerative disorder caused by the GAA repeat expansions of the frataxin (FXN) gene, which results in decreased expression of FXN, a mitochondrial protein critical for iron-sulfur cluster assembly and mitochondrial function. Patients with FRDA display neurological deficits, including progressive gait ataxia, dysarthria, areflexia, and motor weakness. Additional features include cardiomyopathy and diabetes. Although various approaches have been evaluated to improve clinical symptoms of FRDA, there is no effective treatment available to date. Notably, excess iron in brain mitochondria is consistently observed in FRDA patients and animal models of FRDA. Since increased iron generates cytotoxic oxidative stress and disruption of cellular/subcellular iron utilization, reversal of abnormal iron buildup in the mitochondria could ameliorate neurological symptoms of FRDA. Indeed, a therapy that aims to reduce mitochondrial iron has proven successful in mitigating iron-mediated toxicity in the heart. However, this approach does not provide therapeutic benefits for neurological problems in FRDA since current FDA-approved iron chelators neither cross the blood-brain barrier nor access the mitochondrial iron pool. Also, these chelators have demonstrated significant toxicities, such as myelosuppression and neutropenia, which limit their long-term use in neurological disorders. Thus, there is a major unmet need for a new class of mitochondria-accessible, BBB- crossing iron transporters that resolve brain mitochondrial iron accumulation and improve neurobehavioral deficits in FRDA. Earlier we demonstrated that hinokitiol, a small molecule with high iron binding affinity and cell permeability, corrects abnormal iron buildup across the mitochondrial membrane (i.e., low mitochondrial iron and high cytosolic iron) caused by genetic deficiency in mitochondrial iron transporters. Unlike other iron chelators that become hydrophilic after binding to iron (e.g., deferiprone), the iron-hinokitiol complex remains lipophilic and can thereby export excess iron out of the mitochondria along the concentration gradient across the membrane, including the brain. These findings prompted us to question if hinokitiol could reverse mitochondrial iron overload in the brain. Inspired by our recent progress and preliminary data, we now look to therapeutic potential of hinokitiol in correcting mitochondrial iron overload in the brain, which otherwise worsens neurological impairments in FRDA. Thus, the underlying hypothesis in this grant application is that hinokitiol mobilizes and redistributes excess iron from the brain mitochondria to cytosol and prevents oxidative damage, thereby restoring neurological deficits in FRDA. The specific aims are to determine: i) the neuroprotective effect of hinokitiol in a mouse model of FRDA and ii) the effect of hinokitiol on mitochondrial function and its safety in FRDA mice in comparison with other relevant FDA-approved iron chelators. Our studies will provide a new therapeutic strategy to reverse abnormal accumulation of mitochondrial iron and correct neurotoxicity of FRDA, which is unresolved to date.