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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

基本信息

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
项目类别：
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

项目摘要

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，线粒体不再在其中运行有效地产生三磷酸腺苷，通常是由于氧化的一个或多个成分出现问题磷酸化机器。表现为脑病的线粒体疾病的发生率为1/5000 活产，通常在生命的头几年是致命的。这些疾病的遗传原因和临床过程脑病，如复杂I缺乏症，是很好的描述。对这些疾病的有效治疗疾病受到我们对驱动神经元衰退的病理机制缺乏机械性理解的限制，超越了已知的复合体-I生物能量赤字。我们之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。残基产生不可逆的修饰，2-琥珀酸半胱氨酸(2SC)，也称为蛋白质琥珀酸化。线粒体复合体I的Ndufs4基因敲除小鼠模型中富马酸和蛋白质琥珀酸化增加缺乏症。我们证明了α-酮戊二酸脱氢酶(α-)的一个成分的琥珀酸化。 KGDH)复合体会削弱该复合体的酶活性。这导致琥珀酰辅酶A产生减少，并损害底物水平的磷酸化，以产生急需的GTP/ATP。我们假设新陈代谢复合体I丢失引起的酸中毒使α-KG重定向生成2-羟基戊二酸。我们预测这会影响受影响神经元的表观遗传格局。在Ndufs4基因敲除小鼠中，其他非神经细胞的柠檬酸循环也受到影响。我们展示了初步数据显示产生衣康酸的能力受损，衣康酸是一种重要的抗炎药物代谢物。考虑到小胶质细胞聚集在神经病理损伤的中心，这一点很明显。我们的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，这可能在受病理影响最严重的区域加速生化破坏。要解决这些具体问题病理机制我们概述了针对性的治疗方法，应该减少神经病理的驱动因素。