Restoration of mitochondrial function by small-molecule iron transporter in Friedreich’s ataxia

小分子铁转运蛋白在弗里德赖希共济失调中恢复线粒体功能

基本信息

批准号：
10451180
负责人：
Jonghan Kim
金额：
$ 19.56万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10451180
关键词：
Acute Affect Affinity Animal Model Applications Grants Binding Biogenesis Blood - brain barrier anatomy Blood Chemical Analysis Brain Brain region Cardiomyopathies Cells Chelating Agents Clinical Complex Cytosol Data Dexrazoxane Diabetes Mellitus Disease Dose Drug Kinetics Dysarthria Enzymes Excision Excretory function FDA approved Friedreich Ataxia Gait Ataxia Genes Genetic Heart Histopathology Impairment Inherited Investigation Iron Iron Chelating Agents Iron Chelation Iron Overload Liver Mediating Membrane Membrane Potentials Mitochondria Mitochondrial Proteins Motor Mus Myelosuppression Nerve Degeneration Neurodegenerative Disorders Neurologic Neurologic Deficit Neurologic Dysfunctions Neurologic Symptoms Neutropenia Oxidative Stress Oxygen Consumption Parkinson Disease Patients Pattern Permeability Pharmaceutical Preparations Production Radioisotopes Renal function Reporting Research Respiratory Chain Safety Science Severity of illness Sulfur Symptoms Testing Therapeutic Time Tissue Banks Tissues Toxic effect Water blood-brain barrier crossing brain tissue cytotoxic effective therapy frataxin human model hydrophilicity improved iron deficiency lipophilicity mitochondrial dysfunction mitochondrial membrane mouse model nervous system disorder neurobehavioral neurotoxicity novel therapeutic intervention oxidative damage prevent response restoration safety assessment small molecule

项目摘要

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.

项目摘要/摘要 Friedreich的共济失调（FRDA）是由GAA重复引起的遗传常染色体神经退行性疾病 Frataxin（FXN）基因的膨胀，导致FXN的表达降低，一种线粒体蛋白对于铁硫簇组装和线粒体功能至关重要。 FRDA患者显示神经系统缺乏症，包括进行性共济失调，构音障碍，阿雷弗利亚和运动无力。其他功能包括心肌病和糖尿病。尽管已经评估了各种方法以改善临床症状在FRDA中，迄今为止尚无有效的治疗方法。值得注意的是，大脑线粒体中的铁超过铁是在FRDA患者和FRDA的动物模型中始终观察到。由于铁增加产生细胞毒性氧化应激和细胞/亚细胞铁利用的破坏，异常累积的逆转线粒体可以改善FRDA的神经系统症状。确实，一种旨在减少的疗法线粒体铁已被证明成功地减轻了铁介导的心脏毒性。但是，这种方法由于当前经FDA批准的铁，因此无法为FRDA的神经问题提供热益处天体既不穿过血脑屏障，也没有进入线粒体铁池。另外，这些螯合剂有表现出明显的毒性，例如骨髓抑制和中额减少症，这限制了它们的长期使用在神经系统疾病中。那是一个主要的未满足的需求，需要一类新的线粒体访问，bbb-- 跨越铁的脑部线粒体铁积累并改善神经行为的交叉转运蛋白 FRDA的缺陷。早些时候，我们证明了一种具有高铁结合亲和力和细胞的小分子渗透性，纠正在线粒体膜上的异常铁堆积（即，线粒体铁和低的线粒体和高胞质铁）由线粒体铁转运蛋白的遗传缺乏引起。与其他铁螯合剂不同与铁结合后，这会变成亲水性（例如脱氟酮），铁基硫醇复合物保持亲脂性和因此，沿膜上的浓度梯度从线粒体中出口超过铁，包括大脑。这些发现促使我们质疑Hinokitiol是否可以逆转线粒体铁超载受到我们最近的进度和初步数据的启发，我们现在寻求治疗潜力在校正大脑中线粒体铁超负荷时，Hinokitiol否则会使神经系统恶化 FRDA的障碍。这就是本赠款申请中的基本假设是Hinokitiol动员和重新分布超过铁从脑线粒体到细胞质的铁并防止氧化损伤，从而恢复 FRDA的神经系统防御。具体目的是确定：i）Hinokitiol在A中的神经保护作用 FRDA和II的小鼠模型）Hinokitiol对线粒体功能及其在FRDA小鼠中的安全性的影响与其他相关FDA批准的铁螯合剂的比较。我们的研究将提供新的治疗策略逆转线粒体铁的异常积累和FRDA的纠正神经毒性，这尚未解决迄今为止。