Investigating Citric Acid Cycle Perturbations in Complex I Deficient Mitochondrial Encephalopathy

研究复合物 I 缺陷型线粒体脑病中柠檬酸循环的扰动

• 批准号: 10609528
• 负责人: Norma Frizzell
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609528
• 关键词: Acceleration; Address; Affect; Anti-Inflammatory Agents; Ataxia; Basal Ganglia; Biochemical; Bioenergetics; Brain; Brain Stem; Bypass; Cells; Chemicals; Citric Acid Cycle; Clinical; Complex; Cysteine; Data; Defect; Developmental Delay Disorders; Disease; Encephalopathies; Engineering; Epigenetic Process; Esters; Exhibits; Fumarates; Functional disorder; Generations; Genes; Genetic; Gliosis; Guanosine Triphosphate; Histone H3; Human; Impairment; Infiltration; Inflammation; Inflammatory; Ketoglutarate Dehydrogenase Complex; Knock-out; Knockout Mice; Lactic Acidosis; Leigh Disease; Lesion; Life; Link; Live Birth; Lysine; Malate Dehydrogenase; Mediating; Metabolic acidosis; Metabolism; Microglia; Mitochondria; Mitochondrial Diseases; Mitochondrial complex I deficiency; Modeling; Modification; Mutation; Neuroglia; Neurons; Oxidative Phosphorylation; Pathologic; Pathology; Peptides; Permeability; Phagocytes; Phenotype; Phosphorylation; Post-Translational Protein Processing; Production; Proteins; Reaction; Reporting; Resolution; Respiratory Chain; Role; Seizures; Severities; Site; Therapeutic; alpha ketoglutarate; demethylation; design; effective therapy; histone demethylase; histone methylation; individualized medicine; insight; mouse model; neuroinflammation; neuron loss; neuropathology; novel; olfactory bulb; prevent; respiratory; succinyl-coenzyme A; targeted treatment; transcription regulatory network

ABSTRACT Mitochondrial diseases are respiratory chain disorders in which the mitochondria are no longer operating efficiently to produce ATP, usually due to a problem with one or more components of the oxidative phosphorylation machinery. Mitochondrial diseases manifesting as encephalopathies occur at a rate of 1 in 5000 live births and are often fatal in the first few years of life. The genetic cause and clinical course of these encephalopathies, e.g., Complex I deficient Leigh Syndrome, are well-described. The effective treatment of these diseases is limited by our lack of mechanistic understanding of pathomechanisms that drive neuronal decline, beyond the known Complex-I bioenergetic deficit. We have previously described the reaction of the citric acid cycle metabolite fumarate with protein cysteine residues to generate an irreversible modification, 2-succinocysteine (2SC), also known as protein succination. Fumarate and protein succination increase in the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency. We demonstrate that the succination of a component of the α-ketoglutarate dehydrogenase (α- KGDH) complex impairs the enzymatic activity of this complex. This results in decreased succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP/ATP. We hypothesize that metabolic acidosis derived from the Complex I loss redirects α-KG toward 2-hydroxyglutarate production. We predict that this influences the epigenetic landscape in the affected neurons. The citric acid cycle of other non-neuronal cells are also impacted in the Ndufs4 knockout mouse. We show preliminary data to demonstrate an impaired ability to produce itaconate, an important anti-inflammatory metabolite. This is significant given the accumulation of microglia in the center of neuropathological lesions. Our novel hypotheses link specific citric acid cycle perturbations to the chemical modifications of proteins that may accelerate the biochemical damage within the regions most affected by pathology. To address these specific pathomechanisms we outline targeted therapeutic approaches that should reduce the drivers of neuropathology.

摘要 线粒体疾病是呼吸链疾病，其中线粒体不再运作 有效地产生ATP，通常是由于一个或多个组成部分的氧化问题， 磷酸化机制表现为脑病的线粒体疾病的发生率为1/5000 活产，往往在生命的头几年是致命的。这些的遗传原因和临床过程 脑病，例如，复合物I缺乏的Leigh综合征，已被充分描述。有效治疗这些 疾病的局限性在于我们缺乏对驱动神经元衰退的病理机制的机械理解， 超过了已知的复合体I生物能量缺陷。 我们先前已经描述了柠檬酸循环代谢产物富马酸与蛋白质半胱氨酸的反应 在一些实施方案中，蛋白质可以通过一个或多个氨基酸残基来产生不可逆的修饰，2-琥珀半胱氨酸（2SC），也称为蛋白质琥珀酸化。 线粒体复合物I的Ndufs 4敲除小鼠模型中富马酸和蛋白琥珀酸化增加 缺陷我们证明了α-酮戊二酸脱氢酶（α-Ketoglutarate dehydrogenase，α- KGDH）复合物损害该复合物的酶活性。这导致琥珀酰辅酶A的产生减少， 并损害底物水平磷酸化以产生急需的GTP/ATP。我们假设新陈代谢 由复合物I损失引起的酸中毒将α-KG重定向至2-羟基戊二酸的产生。我们预测 这会影响受影响神经元的表观遗传景观。 其他非神经元细胞的柠檬酸循环也在Ndufs 4敲除小鼠中受到影响。我们表明 初步数据表明，受损的能力，产生衣康酸，一个重要的抗炎 代谢物。考虑到小胶质细胞在神经病理学病变中心的积累，这是重要的。我们 新的假说将特定的柠檬酸循环扰动与蛋白质的化学修饰联系起来， 加速受病理影响最严重的区域内的生化损伤。为了解决这些具体问题， 病理机制，我们概述了有针对性的治疗方法，应该减少神经病理学的驱动因素。