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

• 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
• 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

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‘s共济失调(FRDA)是一种由GAA重复引起的遗传性常染色体退行性疾病 Frataxin(FXN)基因的扩增，导致线粒体蛋白FXN的表达下降 对铁-硫簇组装和线粒体功能至关重要。FRDA患者表现为神经功能障碍 缺陷，包括进行性步态共济失调、构音障碍、反射障碍和运动无力。其他功能包括 心肌病和糖尿病。尽管已经对各种方法进行了评估以改善临床症状 对于FRDA，到目前为止还没有有效的治疗方法。值得注意的是，大脑线粒体中过量的铁是 在FRDA患者和FRDA动物模型中一致观察到。由于铁含量增加会产生细胞毒性 氧化应激和细胞/亚细胞铁利用的中断，逆转铁的异常积聚 线粒体可改善FRDA的神经症状。事实上，一种旨在减少 线粒体铁已被证明在减轻铁介导的心脏毒性方面取得了成功。然而，这种方法 不能为FRDA的神经问题提供治疗益处，因为目前FDA批准的铁 螯合剂既不能穿过血脑屏障，也不能进入线粒体铁池。此外，这些螯合剂还具有 显示出严重的毒性，如骨髓抑制和中性粒细胞减少，这限制了它们的长期使用 在神经性疾病方面。因此，对一种新的线粒体可获得的BBB-需求存在着重大的未得到满足的需求。 跨铁转运体解决脑线粒体铁蓄积和改善神经行为 FRDA中的赤字。早些时候，我们证明了Hinokitiol，一种具有高铁结合亲和力的小分子和细胞 通透性，纠正跨线粒体膜的异常铁积聚(即，低线粒体铁和 由线粒体铁转运体遗传缺陷引起的高胞质铁)。与其他铁络合剂不同 在与铁结合后变得亲水性(例如，去铁酮)，铁-脑磷脂复合体保持亲脂性和 从而可以沿着跨膜的浓度梯度将多余的铁从线粒体输出， 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 在大脑里。受我们最近的进展和初步数据的启发，我们现在期待着治疗的潜力 Hin okitiol纠正大脑中线粒体铁超载，否则会恶化神经 FRDA中的减值。因此，在这项赠款申请中的基本假设是，hiokitiol动员和 将多余的铁从大脑线粒体重新分配到胞浆中，防止氧化损伤，从而恢复 FRDA的神经缺陷。其具体目的是确定：i)Hinokitiol对脑出血患者的神经保护作用 FRDA小鼠模型及II)Hin okitiol对FRDA小鼠线粒体功能的影响及其安全性 与FDA批准的其他相关铁络合剂进行比较。我们的研究将提供一种新的治疗策略 逆转线粒体铁异常蓄积，纠正FRDA的神经毒性，尚未解决 到目前为止。