Molecular Pathogenesis of Coenzyme Q10 Deficiency

辅酶 Q10 缺乏症的分子发病机制

• 批准号: 7361460
• 负责人: MICHIO HIRANO
• 金额: $ 40.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-10 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7361460
• 关键词: ATP Synthesis Pathway; Amyotrophic Lateral Sclerosis; Anabolism; Antioxidants; Apoptosis; Ascorbic Acid; Benzoquinones; Cell membrane; Cells; Cerebellar Ataxia; Coenzyme Q10; Collaborations; Complex; Condition; Cultured Cells; Defect; Diagnosis; Disease; Electron Transport Complex III; Electrons; Enzymes; Family; Fibroblasts; Functional disorder; Gene Mutation; Genes; Genetic; Hereditary Disease; Human; Human Cloning; In Vitro; Individual; Infant; Inherited; Kidney; Kidney Diseases; Leigh Disease; Lipid Peroxidation; Lipids; Membrane; Missense Mutation; Mitochondria; Mitochondrial Diseases; Mitochondrial Respiratory Chain Deficiencies; Molecular; Multienzyme Complexes; Mus; Mutation; Myopathy; NADH dehydrogenase (ubiquinone); Natural regeneration; Neurodegenerative Disorders; Numbers; Oral; Oxidative Phosphorylation; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Physical condensation; Plasmids; Predisposition; Process; Production; Proteins; Range; Reactive Oxygen Species; Relative (related person); Reporting; Respiration; Respiratory Chain; Severities; Siblings; Side; Single Strand Break Repair; Spain; Specificity; Succinate dehydrogenase (ubiquinone); Supplementation; Tail; Testing; Tissues; Transferase; Ubiquinone; Universities; Yeasts; analog; autosomal recessive trait; base; benzoquinone; cell growth; clinical phenotype; cytochrome c; decaprenyl pyrophosphate synthetase; functional restoration; human disease; hydroxybenzoate; improved; infancy; isoprenoid; mouse model; mutant; novel; prevent; proband; professor; treatment trial

DESCRIPTION (provided by applicant): Coenzyme Q10 (CoQ10) is a small lipophillic molecule composed of a benzoquinone ring and a hydrophobic isoprenoid tail and is present in virtually all cell membranes. In the mitochondrial respiratory chain, CoQ10 is vital for the transport of electrons from complex I (NADH-ubiquinone oxidoreductase) and complex II (succinate-ubiquinone oxidoreductase) to complex III (ubiquinol-cytochrome c reductase). It is also an antioxidant, membrane stabilizer, and modulator of apoptosis. Human CoQ10-deficiency has been associated with four clinical phenotypes: an encephalomyopathy, infantile encephalomyopathy with renal dysfunction, cerebellar ataxia, and pure myopathy. We have identified 38 patients from 33 families with CoQ10-deficiency. Patients with all forms of CoQ10-deficiency have improved with oral supplementation, therefore recognition of this treatable genetic condition is important. Last year, we reported the first mutations responsible for primary CoQ10-deficiency; in two siblings with the infantile form of CoQ10 deficiency, we identified a homozygous missense mutation in the COQ2 gene which encodes para-hydroxybenzoate-polyprenyl transferase, the enzyme responsible for the condensation of the isoprenoid side chains to the benzoquinone ring. In another infant with fatal Leigh syndrome and nephropathy, we identified compound heterozygous mutations in the PDSS2 gene encoding subunit 2 of decaprenyl diphosphate synthase. In addition, in a family with four individuals with cerebellar ataxia and CoQ10 deficiency, we identified a pathogenic mutation in the APTX gene, which encodes a protein involved in single-strand break repair. Thus, our studies have revealed mutations in CoQ10 biosynthetic genes causing primary CoQ10 deficiency and an APTX mutation as a cause of secondary CoQ10 deficiency. Not surprisingly, CoQ10 deficiency causes defects of respiratory chain activities (reduced activities of complexes I+III and II+III). The relative importance of respiratory chain defects, ROS production, and apoptosis in the pathogenesis of CoQ10-deficiency is unknown. Based on our preliminary studies, we hypothesize that: 1) genotypic heterogenity contributes to the phenotypic variability of CoQ10-deficiency; 2) levels of oxidative stress, respiratory chain deficiency, and apoptosis differ depending on the genetic cause and severity of CoQ10-deficiency; and 3) CoQ10 and its analogs have variable efficacy in CoQ10-deficiency. To test these hypotheses, we propose the following four specific aims. Aim 1: To identify novel genetic causes of CoQ10 deficiency. Aim 2: To characterize the pathogenic mechanisms of CoQ10-deficiency in cultured cells and rescue cellular dysfunction in CoQ10-deficient cells using CoQ10 and its analogs. Aim 3: To generate and assess a mouse model of CoQ deficiency. Aim 4: In collaboration with Professor Placido Navas, University of Sevilla, Spain, we will characterize CoQ10 biosynthetic genes and mutations in yeast.Narrative Coenzyme Q10 (CoQ10) is a vital molecule required for cells to generate energy and to prevent damage from toxic oxygen radicals. The proposed studies will define the causes and treatments of severe genetic diseases associated with CoQ10 deficiency. Furthermore, the studies may provide important information relevant to ongoing human treatment trials of CoQ10 and related anti-oxidants in more common neurodegenerative diseases including Parkinson disease and amyotrophic lateral sclerosis.

描述（由申请人提供）：辅酶 Q10 (CoQ10) 是一种小亲脂性分子，由苯醌环和疏水性类异戊二烯尾组成，几乎存在于所有细胞膜中。在线粒体呼吸链中，CoQ10 对于从复合物 I（NADH-泛醌氧化还原酶）和复合物 II（琥珀酸泛醌氧化还原酶）到复合物 III（泛醇-细胞色素 c 还原酶）的电子传输至关重要。它也是一种抗氧化剂、膜稳定剂和细胞凋亡调节剂。人类 CoQ10 缺乏症与四种临床表型相关：脑肌病、伴有肾功能障碍的婴儿脑​​肌病、小脑共济失调和单纯肌病。我们已经确定了来自 33 个家庭的 38 名 CoQ10 缺乏症患者。患有各种形式的 CoQ10 缺乏症的患者通过口服补充剂都得到了改善，因此认识到这种可治疗的遗传性疾病很重要。去年，我们报告了第一个导致原发性 CoQ10 缺乏的突变；在两个患有 CoQ10 缺乏症的婴儿兄弟姐妹中，我们发现了 COQ2 基因中的纯合错义突变，该基因编码对羟基苯甲酸酯-聚异戊二烯基转移酶，该酶负责将类异戊二烯侧链缩合到苯醌环上。在另一名患有致命 Leigh 综合征和肾病的婴儿中，我们在编码十异戊二烯二磷酸合酶 2 亚基的 PDSS2 基因中发现了复合杂合突变。此外，在一个有四名患有小脑共济失调和 CoQ10 缺乏症的家庭中，我们发现了 APTX 基因的致病性突变，该基因编码一种参与单链断裂修复的蛋白质。因此，我们的研究揭示了 CoQ10 生物合成基因的突变导致原发性 CoQ10 缺乏，而 APTX 突变则导致继发性 CoQ10 缺乏。毫不奇怪，CoQ10 缺乏会导致呼吸链活性缺陷（复合物 I+III 和 II+III 的活性降低）。呼吸链缺陷、ROS 产生和细胞凋亡在辅酶 Q10 缺乏的发病机制中的相对重要性尚不清楚。根据我们的初步研究，我们假设：1）基因型异质性导致 CoQ10 缺乏的表型变异； 2) 氧化应激、呼吸链缺陷和细胞凋亡的水平因 CoQ10 缺乏的遗传原因和严重程度而异； 3) CoQ10 及其类似物对于 CoQ10 缺乏症具有不同的疗效。为了检验这些假设，我们提出以下四个具体目标。目标 1：确定辅酶 Q10 缺乏症的新遗传原因。目标 2：表征培养细胞中辅酶 Q10 缺乏的致病机制，并使用辅酶 Q10 及其类似物挽救辅酶 Q10 缺陷细胞的细胞功能障碍。目标 3：生成并评估 CoQ 缺乏症小鼠模型。目标 4：与西班牙塞维利亚大学的 Placido Navas 教授合作，我们将表征酵母中 CoQ10 生物合成基因和突变。Narrative 辅酶 Q10 (CoQ10) 是细胞产生能量和防止有毒氧损伤所需的重要分子部首。拟议的研究将确定与 CoQ10 缺乏相关的严重遗传性疾病的原因和治疗方法。此外，这些研究可能提供与正在进行的 CoQ10 和相关抗氧化剂治疗帕金森病和肌萎缩侧索硬化症等更常见神经退行性疾病的人类治疗试验相关的重要信息。