Mechanisms of mitochondrial disease suppression in Ndufs4 knockout mice

Ndufs4基因敲除小鼠线粒体疾病抑制机制

基本信息

批准号：
9307448
负责人：
MATT KAEBERLEIN
金额：
$ 47.97万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307448
关键词：
Acarbose Address Adult Affect Age Animals Attenuated Biochemical Biology Blindness Body Weight decreased Brain Cardiomyopathies Cell Nucleus Cessation of life Child Communication Complex Cytoplasm Deacetylase Defect Disease Disease Progression Encephalopathies FRAP1 gene Failure Genetic Glucosidase Inhibitor Goals Growth Health Homeostasis Human Inherited Interphase Cell Intervention Kidney Diseases Knock-out Knockout Mice Lactic Acidosis Leigh Disease Lethargies Liver Metabolic Mitochondria Mitochondrial Diseases Mitochondrial Electron Transport Complex I Mitochondrial Proteins Molecular Motor Skills Mus Mutation NADH Neonatal Nerve Degeneration Neurologic Nicotinamide Mononucleotide Optics Pathology Patients Pharmaceutical Preparations Pharmacology Phosphorylation Play Process Proteomics Reporting Role Signal Pathway Signal Transduction Sirolimus Symptoms Testing Tissues attenuation base brain tissue clinically relevant effective therapy human disease improved improved outcome infancy inhibitor/antagonist insight intervention effect knockout animal metabolome metabolomics mouse model neurodegenerative phenotype novel therapeutics overexpression phosphoproteomics restoration therapy development

项目摘要

7. Project Summary/Abstract Deficiencies in complex I of the mitochondrial electron transport chain represent an important class of human mitochondrial diseases that include Leigh Syndrome, Leber’s hereditary optic nephropathy, neonatal lactic acidosis, cardiomyopathy, and encephalopathy. Leigh Syndrome is generally regarded as the most common mitochondrial disease of infancy and is characterized primarily by severe neurological defects. There is currently no effective treatment. A mouse model has been developed in which the complex I structural subunit NDUFS4 is knocked-out. Ndufs4-/- mice show a profound neurodegenerative phenotype including retarded growth rate, lethargy, loss of motor skill, blindness, weight loss, and early death. These symptoms are recapitulated in human patients with Ndufs4 mutations, as well as other Leigh Syndrome-associated mutations. We have recently reported that treating Ndufs4-/- mice with the drug rapamycin, a specific inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), results in two to three-fold increase in survival, dramatic attenuation of neurologial defecits, and reduced neurodegeneration. In unpublished studies, we have observed similar effects from the NAD+ precursor nicotinamide mononucleotide (NMN) -glucosidase inhibitor acarbose. The broader goals this proposal to define the mechanistic basis for suppression of mitochondrial disease by rapamycin, NMN, and acarbose in the Ndufs4 knockout (KO) mouse. This will be accomplished broadly by assessing changes in the metabolome and phosphoproteome, and specifically by determining the effects of these interventions on mitochondrial function, mTOR signaling, NAD homeostasis, and activity of the NAD-dependent mitochondrial SIRT3 deacetylase. We will test the specific hypothesis that these intervention act by enhancing SIRT3 activity by creating animals lacking both NDUFS4 and SIRT3 and determining whether this blocks or attenuates rescue of the disease. These studies promise to enhance our understanding of mitochondrial function in the context of complex I deficiency and facilitate the development of interventional strategies to improve the lives of patients with mitochondrial disease.

7。项目摘要/摘要线粒体电子传输链中复合物I的缺陷代表了一类重要的人类线粒体疾病，包括Leigh综合征，Leber的遗传性视神经肾病，新生儿乳酸酸中毒，心肌病和脑病。利综合症通常被认为是最常见的婴儿期的线粒体疾病，主要以严重的神经系统缺陷为特征。有目前没有有效的治疗。已经开发了鼠标模型，其中复合物I结构亚基 NDUFS4被淘汰。 NDUFS4 - / - 小鼠显示出深刻的神经退行性表型，包括智障生长速率，嗜睡，运动技能的丧失，失明，体重减轻和早期死亡。这些符号是在NDUFS4突变的人类患者以及其他Leigh综合征相关的突变中概括。我们最近报告说，用药物雷帕霉素治疗NDUFS4 - / - 小鼠，该药物是特定的抑制剂雷帕霉素络合物1（MTORC1）的哺乳动物靶标会增加生存率2至3倍，在未发表的研究中，我们有观察到NAD+前体烟酰胺单核苷酸（NMN） - 葡萄糖苷酶的相似作用抑制剂acarbose。该提议定义抑制机械基础的更广泛的目标 NDUFS4敲除（KO）小鼠中雷帕霉素，NMN和Acarbose的线粒体疾病。这将是通过评估代谢组和磷光蛋白质组的变化，尤其是通过确定这些干预措施对线粒体功能的影响，mTOR信号传导，NAD稳态， NAD依赖性线粒体SIRT3脱乙酰基酶的活性。我们将检验以下特定假设这些干预行为通过创造缺乏NDUFS4和SIRT3的动物来增强SIRT3活动，以及确定这是阻塞还是减弱疾病的营救。这些研究有望增强我们的在复杂的I缺乏症的背景下，了解线粒体功能并支持的发展改善线粒体疾病患者生活的介入策略。