Understanding the role of mitochondrial UPR-activating mtDNA landscapes in health and longevity.

了解线粒体 UPR 激活 mtDNA 景观在健康和长寿中的作用。

• 批准号: 10172817
• 负责人: DORIS A GERMAIN
• 金额: $ 36.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172817
• 关键词: Affect; Aging; Antioxidants; Binding; Biological; Caloric Restriction; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Congenic Mice; DNA Sequence; Disease; Disease Progression; Estrogen Receptor alpha; Estrogens; Exercise; Family; Female; Genes; Genetic; Genetic Transcription; Genome; Genomics; Health; Health Benefit; Heart; Intervention; Lead; Link; Liver; Longevity; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Mus; Mutation; Nuclear; PPAR alpha; Peptide Hydrolases; Peroxisome Proliferator-Activated Receptors; Proteins; Reactive Oxygen Species; Reporting; Role; SOD2 gene; Stress; Testing; Tissues; combinatorial; estrogen-related receptor; gender difference; genome-wide; health difference; improved; loss of function; male; mouse model; proteotoxicity; response; small hairpin RNA; transcription factor

The results of a recent study suggest an intriguing link between mitochondrial genetics and health. This study used C57BL-nuclear-genome matched conplastic mice, where one strain carries mitochondria from the C57BL background (BL6C57) and the other strain carries the mitochondria from the NZ background (BL6NZB). The authors reported that mice carrying NZB mitochondrial DNA (mtDNA) are healthier and show significant differences in longevity despite sharing the same nuclear genome as the BL6C57 mice. Since the mtDNA of NZB and C57BL6 mice vary by only a few mutations, their findings suggest that small changes in mitochondirla genetics can cause large difference in health and longevity. They reported that these differences correlated with a number of changes that are consistent with the activation of axes of the mitochondrial unfolded protein response (UPRmt) identified in the Germain's lab. One axis is regulated by SIRT3 and FOXO3a, both key regulators of aging. Another axis is regulated by the estrogen receptor alpha (ERα). We also recently reported that small differences in mtDNA sequence can lead to differential activation of the axes of the UPRmt and also that their activation varies between males and females. Our central hypothesis is that the differences between the conplastic mice are due to the ability mtDNA of the BL6NZB to activate the UPRmt and will differ not only between males and females. To test this hypothesis, we propose the following three aims: Specific aim 1: Assess the activation of the UPRmt in tissues in the BL6C57 males and females versus BL6NZB males and females congenic mice. Specific aim 2: Test whether deleting key genes of each UPRmt nodes abolishes the health benefit of the BL6NZB conplastic mice. Specific aim 3: Assess whether interventions known to increase SIRT3, FOXO3a or ERα improve the health and longevity of BL6C57 conplastic mice.

最近的一项研究结果表明，线粒体遗传学和健康之间存在着有趣的联系。本研究 使用C57BL核基因组匹配的共生小鼠，其中一种品系携带C57BL的线粒体 背景(BL6C57)，另一株携带新西兰背景的线粒体(BL6NZB)。这个 作者报告说，携带NZB线粒体DNA(MtDNA)的小鼠更健康，并显示出显著的 尽管与BL6C57小鼠拥有相同的核基因组，但它们的寿命存在差异。因为线粒体DNA NZB和C57BL6小鼠只有几个突变，他们的发现表明，线粒体的微小变化 基因可能会导致健康和寿命方面的巨大差异。他们报告说，这些差异与 与线粒体未折叠蛋白的轴的激活相一致的一些变化 在日耳曼实验室确定的响应(UPRmt)。一个轴由SIRT3和FOXO3a调节，这两个键都是 老龄化的监管者。另一个轴受雌激素受体α(ERα)的调节。我们最近还报道了 线粒体DNA序列的微小差异可以导致UPRmt轴的差异激活，还 它们的激活在雄性和雌性之间是不同的。我们的中心假设是 可再生小鼠是由于BL6NZB的线粒体DNA激活UPRmt的能力而导致的，不同的不仅是 在雄性和雌性之间。为了验证这一假设，我们提出了以下三个目标： 具体目标1：评估BL6C57男性和女性与BL6NZB患者组织中UPRmt的激活 雄性和雌性同源基因小鼠。 具体目标2：测试删除每个UPRmt节点的关键基因是否取消了UPRmt节点的健康益处 BL6NZB共生小鼠。 具体目标3：评估已知增加SIRT3、FOXO3a或ERα的干预措施是否改善健康 和BL6C57共育小鼠的寿命。