Regulating mtDNA and mtRNA dynamics by the mitochondrial AAA+ Lon protease

通过线粒体 AAA Lon 蛋白酶调节 mtDNA 和 mtRNA 动力学

基本信息

批准号：
9187845
负责人：
CAROLYN K SUZUKI
金额：
$ 19.88万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187845
关键词：
ATP Hydrolysis ATP phosphohydrolase ATP-Dependent Proteases Aging Bacteria Bacterial Chromosomes Binding Binding Proteins Biogenesis Biological Assay Bone structure Cardiovascular Diseases Cataract Cell Survival Cerebrum Complex Cultured Cells DNA DNA Binding DNA Maintenance DNA Sequence Alteration DNA biosynthesis DNA copy number DNA-Binding Proteins Data Defect Dental Dentition Disease Embryo Enzymes Escherichia coli Fission Yeast Fluorescent in Situ Hybridization Functional disorder Gene Expression Genes Genetic Transcription Genetic study Genome Genomics Health Hearing Heart Diseases Human Immunoprecipitation In Vitro Intellectual functioning disability Knock-out Letters Link Maintenance Mammals Mass Spectrum Analysis Mediating Mental Retardation Mitochondria Mitochondrial DNA Mitochondrial RNA Molecular Chaperones Mus Mutation Nerve Degeneration Normal Cell Oxidative Phosphorylation Parents Pathogenicity Patients Peptide Hydrolases Phenotype Physiological Process Property Proteins Proteolysis Publications Publishing RNA RNA Binding RNA immunoprecipitation sequencing Respiration Respiratory Chain Ribosomes Role Saccharomyces cerevisiae Saccharomycetales Site System Transcript Translations acronyms cerebro-oculo-dento-auriculo-skeletal syndrome deep sequencing developmental disease ds-DNA endopeptidase La exome experimental study gastrulation insight lymphoblastoid cell line mitochondrial dysfunction mitochondrial genome mitochondrial messenger RNA mutant overexpression proband protein aggregation protein protein interaction public health relevance reconstitution single molecule skeletal tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): CODAS syndrome is a multi-system developmental disorder characterized by intellectual disability, cataracts, and abnormalities in dentition, hearig and skeletal structure. CODAS is an acronym for cerebral, ocular, dental, auricular and skeletal anomalies. Using whole exome analysis and direct genomic sequencing, we recently demonstrated that mutations in the LONP1 gene are associated with CODAS syndrome. LONP1 encodes mitochondrial Lon, which is an ATP-dependent protease, a chaperone and a DNA-binding protein. Lon binds directly to DNA and RNA, and is required for the maintenance and expression of mitochondrial DNA (mtDNA). As mtDNA encodes essential subunits of the oxidative phosphorylation system, changes in Lon function at the mitochondrial genome will impact cellular energetics and cell survival. Our published and unpublished findings demonstrate that the majority of LonCODAS mutations cluster within the AAA+ domain of Lon, which mediates DNA- and RNA- binding as well as ATP hydrolysis. This project focuses on the direct and specific role of Lon in mitochondrial gene expression (i.e. transcription and translation). The results obtained will provide key mechanistic insights into how Lon dysfunction in these processes contributes to the pathophysiology of CODAS syndrome. In addition, the discovery that CODAS syndrome is linked to naturally occurring mutations in mitochondrial Lon, provides a unique and powerful opportunity to elucidate the diverse functions of this multi-functional enzyme in both human health and common disease processes such as neurodegeneration, oncogenesis, cardiac disease as well as aging.

描述（由适用提供）：CODAS综合征是一种多系统发育障碍，其特征在于牙齿残疾，白内障和牙齿，Hearig和骨骼结构的异常。 CODA是脑，眼，牙，耳和骨骼异常的首字母缩写。使用整个外显子分析和直接基因组测序，我们最近证明了LONP1基因中的突变与CODAS综合征有关。 LONP1编码线粒体LON，它是ATP依赖性蛋白，链酮和DNA结合蛋白。 LON直接与DNA和RNA结合，是线粒体DNA（mtDNA）的维持和表达所必需的。当mtDNA编码氧化磷酸化系统的基本亚基时，线粒体基因组的LON功能的变化将影响细胞能量和细胞存活。我们发表的未发表的发现表明，LON的AAA+结构域中的大多数Loncodas突变集群介导DNA和RNA结合以及ATP水解。该项目着重于LON在线粒体基因表达（即转录和翻译）中的直接和特定作用。获得的结果将提供关键的机理见解，以了解这些过程中的LON功能障碍如何有助于CODAS综合征的病理生理。此外，发现CODAS综合征与线粒体LON的自然发生的突变有关，这提供了一个独特而有力的机会，可以阐明这种多功能酶在人类健康和常见疾病过程中的潜水功能，例如神经变性过程，肿瘤发生，心脏病，心脏病和衰老。