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 对于铁硫簇组装和线粒体功能至关重要。 FRDA 患者表现出神经系统症状 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。附加功能包括 心肌病和糖尿病。尽管已经评估了各种改善临床症状的方法 FRDA 指出，迄今为止尚无有效的治疗方法。值得注意的是，大脑线粒体中过量的铁 在 FRDA 患者和 FRDA 动物模型中一致观察到。由于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 线粒体可以改善 FRDA 的神经系统症状。事实上，一种旨在减少 线粒体铁已被证明可以成功减轻铁介导的心脏毒性。然而，这种方法 由于目前 FDA 批准的铁剂对 FRDA 中的神经系统问题没有提供治疗益处 螯合剂既不穿过血脑屏障也不进入线粒体铁池。此外，这些螯合剂还具有 表现出显着的毒性，例如骨髓抑制和中性粒细胞减少症，这限制了其长期使用 在神经系统疾病中。因此，对一类新的线粒体可接近的 BBB- 的需求存在重大未满足的需求。 穿过铁转运蛋白，解决大脑线粒体铁积累并改善神经行为 FRDA 的赤字。早些时候我们证明了扁柏酚，一种具有高铁结合亲和力和细胞活性的小分子。 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 高胞质铁）由线粒体铁转运蛋白遗传缺陷引起。与其他铁螯合剂不同 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 因此可以沿着跨膜的浓度梯度将过量的铁从线粒体中输出， 包括大脑。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 在大脑中。受我们最近的进展和初步数据的启发，我们现在寻找治疗潜力 桧酚可纠正大脑中线粒体铁超载，否则会导致神经系统恶化 FRDA 的损害。因此，本次拨款申请的基本假设是扁柏酚动员并 将多余的铁从脑线粒体重新分配到细胞质中，防止氧化损伤，从而恢复 FRDA 中的神经功能缺陷。具体目标是确定：i) 扁柏酚对神经保护作用 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。