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.
