The Mitochondrial Genotype and Phenotype of Extreme Longevity

长寿的线粒体基因型和表型

• 批准号: RGPIN-2019-05992
• 负责人: Blier, Pierre
• 金额: $ 5.97万
• 依托单位: Université du Québec à Rimouski
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713456
• 关键词: Mitochondrial; Genotype; Phenotype; Extreme; Longevity

Aging processes have been addressed from two different perspectives: Evolutionary Biology and Cellular Physiology (mechanistic approach). A clear identification of physiological and biochemical processes involved in setting the rate as well as the limits of aging, precludes the possibility of formulating a coherent and unified theory. Among the different mechanistic hypotheses of aging, the mitochondrial oxidative stress theory of aging is probably the most supported. Whether or not this hypothsis is true, a large consensus exists on mitochondria being a hub of metabolic processes involved in aging. My research program, which has been supported by NSERC (Discovery) for more than two decades, is dedicated to document evolutionary plasticity of mitochondrial structure and functions in the animal kingdom and to scrutinize the role and importance of mitochondrial DNA evolution in metabolic adaptation to specific environments and conditions. I recently focused on implication of mitochondria in the modulation of life span. I chose a comparative approach using bivalves as an animal model. This model includes the longest-lived complex animal species on earth, Arctica islandica, which can reach 507 years. This record has been obtained by an individual from an Icelandic population. In other populations from the North Atlantic (Europe and North America), the maximum life span can vary between 40 years to 200-300 years. Other taxonomically close species have maximum life span ranging from a few years to close to 150 years. I therefore have access to a two-dimensional comparative model: comparison of different species within a wide range of maximum life spans (from 4 years to 507 years), and comparison of different populations of A. islandica characterized by standard maximum life span ranging from 35 to 400 years (see Blier et al. Seminars in Cell and Developmental Biology, 2017). We previously observed a clear link between mitochondrial membrane robustness to oxidative stress (expressed as fatty acid content and Peroxidation Index) ROs management and the maximum lifespan in marine bivalves (Munro & Blier, 2012). We also demonstrated that mitochondria from the long-lived species generate a much lower efflux of H2O2 than short-lived species ( Munro et al. 2013). Based on these observations, we will deepen our analysis on the link between structure and function of mitochondria and longevity in animals. Some hypotheses have been put forward to link mitochondrial structure and function to lifespan and the aging process. Among them, 1) decline in the regulation of mechanisms of apoptosis induction 2) impairment of ROS management 3) instability of the Electron Transport System (ETS) supercomplexes. My students, trainees and I will characterize the fine structure of mitochondrial membranes (lipidomique analysis of membranes: phospholipids, sterols, cardiolipin content and structure) and stress responses.

衰老过程从两个不同的角度进行研究：进化生物学和细胞生理学（机械方法）。 明确确定衰老速率和极限所涉及的生理和生化过程，排除了制定连贯且统一的理论的可能性。 在不同的衰老机制假说中，线粒体氧化应激衰老理论可能是最受支持的。 无论这个假设是否正确，人们普遍认为线粒体是衰老过程中代谢过程的枢纽。我的研究项目二十多年来一直得到 NSERC（Discovery）的支持，致力于记录动物界线粒体结构和功能的进化可塑性，并仔细研究线粒体 DNA 进化在代谢适应特定环境中的作用和重要性。环境和条件。我最近关注线粒体在寿命调节中的影响。我选择了一种使用双壳类动物作为动物模型的比较方法。该模型包括地球上最长寿的复杂动物物种Arctica islandica，寿命可达507岁。该记录是由冰岛人获得的。在北大西洋（欧洲和北美）的其他人群中，最长寿命可能在 40 岁到 200-300 岁之间。其他分类学上相近的物种的最长寿命从几年到接近 150 年不等。因此，我可以获得一个二维比较模型：比较不同物种在最大寿命范围（从 4 年到 507 岁）内的比较，以及比较 A. islandica 的标准最大寿命范围为35 至 400 年（参见 Blier 等人，细胞和发育生物学研讨会，2017 年）。我们之前观察到线粒体膜对氧化应激（以脂肪酸含量和过氧化指数表示）的稳健性、RO 管理和海洋双壳类的最大寿命之间存在明显的联系（Munro 和 Blier，2012）。我们还证明，长寿物种的线粒体产生的 H2O2 流出量比短寿命物种低得多（Munro 等人，2013）。基于这些观察，我们将深入分析线粒体的结构和功能与动物寿命之间的联系。 已经提出一些假设将线粒体结构和功能与寿命和衰老过程联系起来。其中，1）细胞凋亡诱导机制的调节下降2）ROS管理受损3）电子传输系统（ETS）超复合物的不稳定性。我和我的学生、学员将描述线粒体膜的精细结构（膜的脂质分析：磷脂、甾醇、心磷脂含量和结构）和应激反应。