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与健康之间存在着有趣的联系。这项研究 使用 C57BL 核基因组匹配的重组小鼠，其中一种品系携带来自 C57BL 的线粒体 背景（BL6C57）和另一个菌株携带来自NZ背景（BL6NZB）的线粒体。这 作者报告说，携带 NZB 线粒体 DNA (mtDNA) 的小鼠更健康，并且表现出显着的 尽管与 BL6C57 小鼠具有相同的核基因组，但寿命存在差异。由于线粒体DNA NZB 和 C57BL6 小鼠仅存在少量突变，他们的发现表明线粒体的微小变化 遗传因素会导致健康和寿命的巨大差异。他们报告说，这些差异相关 具有与线粒体未折叠蛋白轴的激活一致的许多变化 Germain 实验室确定了响应（UPRmt）。一根轴由 SIRT3 和 FOXO3a 调节，两者都是关键 衰老调节剂。另一个轴受雌激素受体α (ERα) 调节。我们最近还报道了 mtDNA 序列的微小差异可能导致 UPRmt 轴的差异激活，并且 它们的激活程度在男性和女性之间存在差异。我们的中心假设是 重组小鼠是由于 BL6NZB 的 mtDNA 激活 UPRmt 的能力造成的，并且不仅会有所不同 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： 具体目标 1：与 BL6NZB 相比，评估 BL6C57 雄性和雌性组织中 UPRmt 的激活情况 雄性和雌性同源小鼠。 具体目标2：测试删除每个UPRmt节点的关键基因是否会消除该节点的健康益处 BL6NZB 畸形小鼠。 具体目标 3：评估已知可增加 SIRT3、FOXO3a 或 ERα 的干预措施是否可以改善健康 和 BL6C57 再生小鼠的寿命。