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The role of the mitochondrial protein dimer CHCHD2/10 in health and disease

线粒体蛋白二聚体 CHCHD2/10 在健康和疾病中的作用

基本信息

批准号：
9807027
负责人：
Giovanni Manfredi
金额：
$ 42.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807027
关键词：
1 year old Address Affect Amino Acid Substitution Area Behavioral Biochemical Biological Markers Body Weight decreased Brain Cardiomyopathies Cells Chronic Complex Crista ampullaris Development Disease Disease Progression Electron Microscopy FRAP1 gene Family Frontotemporal Dementia Genetic Genetic Diseases Genetic Transcription Goals Health Heart Heart Mitochondria Human Inner mitochondrial membrane Knock-in Mouse Knockout Mice Knowledge Link Longevity Mediating Metabolic Metabolism Mitochondria Mitochondrial Diseases Mitochondrial Matrix Mitochondrial Proteins Molecular Molecular Biology Molecular Weight Monitor Morphologic artifacts Morphology Motor Motor Neuron Disease Motor Neurons Mus Muscle Muscle Mitochondria Mutant Strains Mice Mutation Myopathy Names Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuromuscular Diseases Neuromuscular Junction Organ Organelles Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacology Phenotype Plasma Proteins Proteomics Reporting Role Signal Transduction Sirolimus Skeletal Muscle Spinal Stress Swelling System Systemic disease Testing Therapeutic Tissues Transgenic Organisms Vacuole Work biological adaptation to stress dimer disease phenotype dopaminergic neuron improved in vivo loss of function metabolome metabolomics mitochondrial dysfunction molecular marker motor deficit mouse model muscle form mutant novel overexpression paralogous gene premature promoter protein function proteotoxicity response biomarker stress granule therapeutic evaluation transcriptomics

项目摘要

Skeletal muscle, heart, and brain are high-energy requiring tissues that are severely affected by mitochondrial dysfunction. Recently a novel form of genetic disease affecting mitochondria has been associated with mutations in a mitochondrial protein, CHCHD10 (D10), whose function is still largely unknown. Mutant D10 causes severe autosomal dominant mitochondrial diseases, with diverse phenotypic features, ranging from myopathy to motor neuron disease and frontotemporal dementia. We previously showed that in mitochondria D10 forms a dimeric complex with its paralog protein, CHCHD2 (D2). Interestingly, mutations in D2 are also associated with familial neurodegenerative diseases. To study the manifestations and disease mechanisms of mutant D10 in vivo, we have generated a knock in mouse harboring the first pathogenic D10 mutation reported in humans (S59L, corresponding to mouse S55L). In D10S55L mouse muscle and heart mitochondria, D10 and D2 accumulate and aggregate, leading to mitochondrial dysfunction and degeneration. These abnormalities result in a profound integrated mitochondrial stress response (ISRmt), altering transcriptional profiles and metabolism, and ultimately resulting in fatal cardiomyopathy. Conversely, D10 knock out mice do not manifest mtISR and are phenotypically normal, suggesting that D10S55L causes disease through a toxic mechanism and not a loss of function. In this application, we will study the normal function of D10 and D2 and the mechanisms underlying mitochondrial alterations in D10S55L mice. Since D10 mutations cause neurodegeneration in humans, we will also investigate the involvement of the nervous system in D10S55L mice. We will then identify metabolic and molecular biomarkers to help monitor disease course. Lastly, we will test the effects of pharmacological modulation of ISRmt in D10S55L mice as a therapeutic strategy. The impact of this project will be to facilitate rationale approaches to target disease pathogenesis in patients with D10 mutations, which could be extended to other mitochondrial diseases mediated by ISRmt

骨骼肌、心脏和大脑都是需要高能量的组织，线粒体功能障碍最近，一种影响线粒体的新型遗传疾病已经被发现，与线粒体蛋白CHCHD10（D10）的突变有关，其功能是仍然大部分未知。突变体D10导致严重的常染色体显性线粒体疾病，具有不同的表型特征，从肌病到运动神经元疾病，额颞叶痴呆我们先前表明，在线粒体中，D10形成二聚体，与其副产物蛋白CHCHD2（D2）复合。有趣的是，D2的突变也与家族性神经退行性疾病研究其临床表现和发病机制突变体D10在体内，我们已经产生了一个敲在小鼠窝藏的第一个致病性D10 在人类中报告的突变（S59L，对应于小鼠S55L）。在D10S55L小鼠肌肉中和心脏线粒体，D10和D2积累和聚集，导致线粒体功能障碍和退化。这些异常导致了一个深刻的整合线粒体应激反应（ISRmt），改变转录谱和代谢，并最终导致致命的心肌病相反，D10敲除小鼠不表现mtISR，表型正常，表明D10S55L通过毒性机制引起疾病，而不是功能丧失。在本应用中，我们将研究D10和D2的正常功能以及 D10S55L小鼠线粒体改变的潜在机制。由于D10突变导致我们还将研究神经系统在人类神经退行性疾病中的参与， D10S55L小鼠。然后，我们将确定代谢和分子生物标志物，以帮助监测疾病当然了最后，我们将测试ISRmt在D10S55L小鼠中的药理学调节作用，一种治疗策略该项目的影响将是促进合理的方法， D10突变患者的疾病发病机制，这可以扩展到其他 ISRmt介导的线粒体疾病