Anaplerotic Therapy for Mitochondrial Complex I Deficiency

线粒体复合物 I 缺乏症的回补疗法

基本信息

批准号：
10118501
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：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10118501
关键词：
Acidosis Address Affect Anti-Inflammatory Agents Antioxidants Astrocytes Ataxia Basal Ganglia Biochemical Bioenergetics Brain Brain Stem Brain region Cell Death Cells Citric Acid Cycle Clinical Complex Cysteine Data Defect Disease Electron Transport Encephalopathies Epigenetic Process Esters Exhibits Fumarates Functional disorder Gliosis Guanosine Triphosphate Health Histone H3 Immune Impaired cognition Impairment Inflammation Inflammatory Insulin Ketoglutarate Dehydrogenase Complex Knockout Mice Lactic Acidosis Leigh Disease Life Link Live Birth Lysine Malate Dehydrogenase Mediating Metabolic Metabolic acidosis Metabolism Methods Microglia Mitochondria Mitochondrial Diseases Mitochondrial complex I deficiency Modeling Modification Motor Multienzyme Complexes NADH Neurons Oxidative Phosphorylation Pathologic Pathology Pathway interactions Phagocytes Phosphorylation Play Prevention therapy Production Proteins Reaction Reporting Resolution Respiratory Chain Role Seizures Series Severities Succinates Sulfhydryl Compounds Vitamins Work alpha ketoglutarate antioxidant therapy demethylation gene repression histone demethylase improved individualized medicine insight ketoglutarate dehydrogenase motor deficit mouse model neuroinflammation neuron loss neuropathology novel olfactory bulb oxidation prevent respiratory succinyl-coenzyme A

项目摘要

ABSTRACT 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. 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. The clinical course of these encephalopathies, e.g. Leigh Syndrome, are well-described, the precise biochemical alterations that contribute to neuropathology, beyond the ATP defect, are less understood. 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). We have described increased 2SC in several models, including the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency. Preliminary data shown in this proposal links the succination of a component of the α-ketoglutarate dehydrogenase (α-KGDH) complex to the defective function of this enzyme complex. This results in decreased succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP. We hypothesize that the α-KG is instead converted to 2-hydroxyglutarate under acidic conditions, i.e. lactic acidosis. We predict that this influences the epigenetic landscape in the affected neurons. Further, we note that metabolic acidosis combined with Ndufs4 bioenergetic defect also impacts the activated microglia in the affected regions of the brain, by suppressing production of an anti-inflammatory metabolite. We hypothesize that this leads to unresolved inflammation that may further exacerbate neuronal cell death. Our novel data suggests that citric acid cycle dysfunction plays a key role in mediating the biochemical damage within the regions most affected by pathology. In this proposal we outline several targeted anaplerotic therapies, and an improved delivery method, that should ameliorate some of these biochemical defects. Importantly, since these compounds are non-toxic fuels, they can be combined with existing vitamin/antioxidants to support neuronal health.

抽象的表现为脑病的线粒体疾病的发生率为五千分之一的活产儿，并且通常是生命最初几年致命的线粒体疾病是线粒体呼吸链疾病。不再有效地生产 ATP，通常是由于 ATP 的一种或多种成分出现问题这些脑病的临床过程，例如利氏综合征，详细描述了除 ATP 缺陷之外的导致神经病理学的精确生化改变，较少被理解。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生成不可逆修饰，2-琥珀酰半胱氨酸（2SC）我们已经描述了增加的2SC。在多种模型中，包括线粒体复合物 I 缺陷的 Ndufs4 敲除小鼠模型。该提案中显示的初步数据将 α-酮戊二酸成分的琥珀化联系起来脱氢酶（α-KGDH）复合物的缺陷导致该酶复合物的功能下降。琥珀酰 CoA 的产生，并削弱底物水平的磷酸化以产生急需的 GTP。促进α-KG在酸性条件下转化为2-羟基戊二酸，即乳酸性酸中毒。我们预测这会影响受影响神经元的表观遗传景观，此外，我们注意到代谢。酸中毒与 Ndufs4 生物能缺陷相结合也会影响受影响区域的活化小胶质细胞通过抑制抗炎代谢物的产生，我们发现这会导致大脑的炎症。我们的新数据表明，未解决的炎症可能会进一步加剧神经元细胞死亡。酸循环功能障碍在介导受影响最严重的区域内的生化损伤中起着关键作用在本提案中，我们概述了几种靶向回补疗法以及改进的递送方法，重要的是，这应该可以改善其中一些生化缺陷，因为这些化合物是无毒的。作为燃料，它们可以与现有的维生素/抗氧化剂结合以支持神经系统健康。