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: 9752438
• 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/9752438
• 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; Estrogen Receptors; 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.

最近的一项研究的结果表明，线粒体遗传学与健康之间存在着有趣的联系。这项研究 使用的C57BL核基因组匹配的构膜塑料小鼠，其中一种菌株从C57BL中携带线粒体 背景（BL6C57）和其他菌株从NZ背景（BL6NZB）带有线粒体。 作者报告说，携带NZB线粒体DNA（mtDNA）的小鼠更健康，并且显示出显着的 长寿差异的差异与BL6C57小鼠共享相同的核基因组。由于mtdna的 NZB和C57BL6小鼠只有几个突变而变化，它们的发现表明线粒体变化很小 遗传学会导致健康和寿命差异很大。他们报告说这些差异相关 与线粒体展开蛋白轴激活相一致的许多变化 在Germain的实验室中确定的响应（UPRMT）。一个轴由SIRT3和FOXO3A调节，两个轴都键 衰老的监管机构。另一个轴由雌激素受体α（ERα）调节。我们最近还报道了 mtDNA序列的微小差异会导致UPRMT轴的差异激活，还会导致 他们的激活范围在男性和女性之间。我们的中心假设是 结构型小鼠是由于BL6NZB激活UPRMT的能力mtDNA所致，不仅会不同 在男性和女性之间。为了检验这一假设，我们提出以下三个目标： 特定目标1：评估BL6C57雄性与女性与BL6NZB的组织中UPRMT的激活 雄性和女性同类小鼠。 特定目标2：测试是否删除每个UPRMT节点的关键基因是否废除了健康的好处 BL6NZB构型小鼠。 特定目标3：评估已知增加SIRT3，FOXO3A或ERα的干预措施是否改善了健康状况 和BL6C57构塑小鼠的寿命。