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.

抽象的线粒体疾病是线粒体不再运作的呼吸链疾病有效地产生 ATP，通常是由于氧化酶的一种或多种成分出现问题表现为脑病的线粒体疾病的发生率为五千分之一。活产，并且在生命的最初几年通常是致命的。这些的遗传原因和临床过程。脑病，例如复合物 I 缺陷型 Leigh 综合征，已有详细描述。由于我们对导致神经衰退的病理机制缺乏机制性的理解，疾病的发展受到限制，超出了已知的 Complex-I 生物能量不足。我们之前描述了柠檬酸循环代谢物富马酸盐与蛋白质半胱氨酸的反应残基产生不可逆的修饰，2-琥珀酰半胱氨酸（2SC），也称为蛋白质琥珀化。线粒体复合物 I 的 Ndufs4 敲除小鼠模型中富马酸和蛋白质琥珀化增加我们证明了α-酮戊二酸脱氢酶（α-）的一个成分的琥珀化作用。 KGDH) 复合物会损害该复合物的酶活性，这会导致琥珀酰辅酶 A 的产生减少，且底物水平磷酸化受损，无法产生急需的 GTP/ATP。由复合物 I 损失引起的酸中毒将 α-KG 转向 2-羟基戊二酸的产生。这会影响受影响神经元的表观遗传景观。我们发现，Ndufs4 敲除小鼠中其他非神经元细胞的柠檬酸循环也受到影响。初步数据表明衣康酸的生产能力受损，衣康酸是一种重要的抗炎药考虑到小胶质细胞在神经病理病变中心的积累，这一点很重要。新的假设将特定的柠檬酸循环扰动与蛋白质的化学修饰联系起来，这可能加速受病理影响最严重的区域内的生化损伤，以解决这些特定问题。我们概述了可减少神经病理学驱动因素的针对性治疗方法。