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

• 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
• 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

 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（由申请人提供）：CODAS综合征是一种多系统发育障碍，其特征为智力残疾、白内障以及牙列、听力和骨骼结构异常。CODAS是脑、眼、牙、耳和骨骼异常的首字母缩写。利用全外显子组分析和直接基因组测序，我们最近证明LONP 1基因突变与CODAS综合征相关。LONP 1编码线粒体Lon，其是ATP依赖性蛋白酶、伴侣蛋白和DNA结合蛋白。Lon直接与DNA和RNA结合，是线粒体DNA（mtDNA）维持和表达所必需的。由于mtDNA编码氧化磷酸化系统的重要亚基，线粒体基因组中Lon功能的变化将影响细胞能量学和细胞存活。我们已发表和未发表的研究结果表明，大多数LonCODAS突变聚集在Lon的AAA+结构域内，其介导DNA和RNA结合以及ATP水解。该项目的重点是Lon在线粒体基因表达（即转录和翻译）中的直接和特异性作用。所获得的结果将提供关键的机制的见解如何在这些过程中的Lon功能障碍有助于CODAS综合征的病理生理学。此外，发现CODAS综合征与线粒体Lon中天然发生的突变有关，这为阐明这种多功能酶在人类健康和常见疾病过程（如神经变性、肿瘤发生、心脏病以及衰老）中的多种功能提供了独特而有力的机会。