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

小分子铁转运蛋白对弗里德赖希共济失调线粒体功能的恢复

基本信息

批准号：
10558616
负责人：
Jonghan Kim
金额：
$ 23.48万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558616
关键词：
Acute Affect Affinity Animal Model Applications Grants Binding Biogenesis Blood Chemical Analysis Brain Brain region Cardiology 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 autosome 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 neuroprotection 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.

项目概要/摘要弗里德赖希共济失调 (FRDA) 是一种由 GAA 重复引起的遗传性常染色体神经退行性疾病 frataxin (FXN) 基因的扩增，导致线粒体蛋白 FXN 的表达减少对铁硫簇组装和线粒体功能至关重要。 FRDA 患者表现出神经功能。缺陷，包括进行性步态共济失调、构音障碍、反射消失和运动无力。尽管已经评估了各种方法来改善临床症状。 FRDA 指出，迄今为止尚无有效的治疗方法，值得注意的是，脑线粒体中铁含量过高。在 FRDA 患者和 FRDA 动物模型中一致观察到，因为增加的铁会产生细胞毒性。氧化应激和细胞/亚细胞铁利用的破坏，逆转细胞内异常铁的积累事实上，线粒体可以改善 FRDA 的神经系统症状，这是一种旨在减少 FRDA 的疗法。线粒体铁已被证明可以成功减轻铁介导的心脏毒性。自目前 FDA 批准的铁剂以来，对于 FRDA 中的神经系统问题没有提供治疗益处螯合剂既不能穿过血脑屏障，也不能进入线粒体铁池。显着的毒性，例如骨髓抑制和中性粒细胞减少症，限制了其长期使用因此，对一类新的线粒体可接近的 BBB- 的需求尚未得到满足。穿过铁转运蛋白，解决大脑线粒体铁积累并改善神经行为之前我们证明了扁柏酚，一种具有高铁结合亲和力和细胞的小分子。渗透性，纠正线粒体膜上异常的铁积累（即线粒体铁含量低和与其他铁螯合剂不同，由线粒体铁转运蛋白遗传缺陷引起的高胞质铁。与铁（例如去铁酮）结合后变得亲水，铁-桧醇复合物仍然是亲脂性的，并且因此可以沿着膜上的浓度梯度将过量的铁从线粒体中输出，这些发现促使我们质疑扁柏酚是否可以逆转线粒体铁超载。受我们最近的进展和初步数据的启发，我们现在正在寻找治疗潜力。桧酚可纠正大脑中线粒体铁超载，否则会恶化神经功能因此，本次拨款申请的基本假设是桧木酚会动员和将过量的铁从脑线粒体重新分配到细胞质中，并防止氧化从而损伤，恢复 FRDA 中的神经功能缺损的具体目的是确定： i) 扁柏酚在 a 中的神经保护作用。 FRDA 小鼠模型和 ii) 日扁柏酚对 FRDA 小鼠线粒体功能及其安全性的影响与 FDA 批准的其他相关铁螯合剂进行比较，我们的研究将提供一种新的治疗策略。逆转线粒体铁的异常积累并纠正尚未解决的 FRDA 神经毒性迄今为止。