Linking mitochondrial variation and lifespan amongst five species of Rodentia

将五种啮齿目动物的线粒体变异与寿命联系起来

• 批准号: 9077372
• 负责人: JOHN M DENU
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9077372
• 关键词: Acetylation; Address; Adult; Affect; Age; Age Factors; Aging; Animals; Biochemical; Biological; Biological Aging; Biology of Aging; Brain; Caloric Restriction; Cell Death; Chemicals; Complex; Data; Deacetylase; Deacetylation; Disease; Electron Transport; Electrons; Energy Metabolism; Enzymes; Evolution; Exhibits; Future; Generations; Grant; Gray unit of radiation dose; Heart; Human; Impairment; Individual; Intervention; Investigation; Knock-out; Life; Link; Liver; Liver Mitochondria; Longevity; Lysine; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial Proteins; Modality; Modeling; Modification; Mole Rats; Mus; Muscle; Muscle Mitochondria; Nature; Oxidative Phosphorylation; Pathology; Pathway interactions; Peptides; Phenotype; Phylogeny; Physiological; Physiology; Play; Population; Post-Translational Protein Processing; Primates; Proteins; Proteome; Protocols documentation; Rattus; Research; Resolution; Respiration; Rodent; Role; Sampling; Site; Spermophilus; Squirrel; System; Testing; Therapeutic Intervention; Time; Variant; Work; age related; animal old age; base; comparative; complex IV; enzyme structure; inhibitor/antagonist; insight; loss of function; mitochondrial dysfunction; mitochondrial metabolism; mouse model; muscle aging; oxidation; pressure; public health relevance; research study; respiratory; senescence; stoichiometry; targeted treatment; trait; young adult

 DESCRIPTION (provided by applicant): Lifespan varies dramatically among even closely related species, as exemplified within groups such as primates and rodents. Despite these disparities in lifespan, recent studies have focused on intra-specific aging pathologies, primarily within the murine system. While mice have provided much insight into aging biology, it is unclear if such a short-lived species lack defenses against senescence that may have evolved in related long- lived species. Many age-related diseases have been linked to mitochondrial dysfunction that are measured by decreased energy generation, structural damage to cellular components, and even cell death. Post translational modifications (PTMs) orchestrate many of the pathways associated with cellular metabolism, and are thought to be a key regulator in biological senescence. Hyperacetylation is one such modification that has been implicated in numerous mitochondrial impairments affecting energy metabolism. Recently, we observed significant hyperacetylation of proteins/enzymes in pathways associated with oxidative phosphorylation due to sirtuin 3 (SIRT3) knockout and elevated SIRT3 expression via caloric restriction - both factors that influence protein acetyl status. Furthermore, caloric restriction ad SIRT3 expression significantly increased electron flux through both complex I and II of the electron transport system (ETS) in muscle of mice, suggesting acetylation status plays a critical role in mitochondrial respiration. When comparing differences between species, preliminary work comparing mice to the long-lived naked mole rat revealed ETS-wide differences, such as lower leak respiration and complex IV activities in the brain and heart of naked mole rats, indicating inherent differences in mitochondrial metabolism. Here, we aim to establish whether hyperacetylation is associated with mitochondrial dysfunction and differences in lifespan between mice, rats, thirteen-lined ground squirrels, grey squirrels and naked mole rats. We will measure flux through the ETS in the muscle and liver of all five species using high-resolution respirometry and substantiate these measurements by measuring isolated complex activities. Next, we will quantify the stoichiometry of peptide acetylation from these samples to determine if they are correlated with both mitochondrial function and lifespan. The research proposed here will elucidate the evolutionary role of acetylation in regulating aging, and establish potential targets as well as validate existing targets for therapeutic interventions. The R03 small-grant mechanism is an excellent fit for the proposed work, as it nicely piggybacks with our ongoing aging studies in the murine model and takes advantage of our recently developed methods to determine site-specific stoichiometry of acetylation in a large proteome.

 描述（由申请人提供）：即使在密切相关的物种之间，寿命也存在显着差异，例如灵长类动物和啮齿动物等群体中的例子，尽管寿命存在这些差异，但最近的研究主要集中在特定的衰老病理学上。 在小鼠系统中，虽然小鼠对衰老生物学提供了很多见解，但尚不清楚这种短命物种是否缺乏在相关长寿物种中进化出的防御能力。许多与年龄相关的疾病与线粒体有关。通过能量产生减少、细胞成分结构损伤甚至细胞死亡来衡量的功能障碍协调了许多与细胞代谢相关的途径，并且被认为是生物衰老的关键调节因子。一个这样的最近，我们观察到由于 Sirtuin 3 (SIRT3) 敲除和热量限制导致的 SIRT3 表达升高，与氧化磷酸化相关的蛋白质途径/酶显着过度乙酰化，这两个因素都是影响蛋白质的因素。此外，热量限制和 SIRT3 表达显着增加了小鼠肌肉中电子传递系统 (ETS) 复合物 I 和 II 的电子通量，表明乙酰化状态在线粒体呼吸中起着关键作用。在比较物种之间的差异时，将小鼠与长寿裸鼹鼠进行比较的初步工作揭示了 ETS 范围内的差异，例如大脑和心脏中较低的漏气呼吸和复杂的 IV 活动。裸鼹鼠，表明线粒体代谢的固有差异，在这里，我们的目标是确定过度乙酰化是否与线粒体功能障碍以及小鼠、大鼠、十三线地松鼠、灰松鼠和裸鼹鼠之间的寿命差异有关。我们将使用高分辨率呼​​吸测量法测量通过所有五个物种的肌肉和肝脏中的 ETS 的通量，并通过测量分离的复杂活动来证实这些测量结果。它们与线粒体功能和寿命相关，这里提出的研究将阐明乙酰化在调节衰老中的进化作用，并建立潜在的目标并验证治疗干预的现有目标。 R03小额资助机制非常适合拟议的工作，因为它很好地配合了我们正在进行的小鼠模型衰老研究，并利用我们最近开发的方法来确定大型蛋白质组中乙酰化的位点特异性化学计量。