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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. 项目总结/文摘