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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738644
• 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.

衰老过程已经从两个不同的角度解决：进化生物学和细胞生理学（机械方法）。对设定速率和衰老局限涉及的物理和生化过程的明确鉴定，排除了制定相干和统一理论的可能性。在衰老的不同机理假设中，衰老的线粒体氧化应激理论可能是最受支持的。无论该假设是否正确，线粒体都存在很大的共识，这是涉及衰老的代谢过程中心。我的研究计划已由NSERC（发现）支持了二十多年，致力于记录线粒体结构和动物界功能的进化可塑性，并仔细检查线粒体DNA在对特定环境和条件中代谢适应的线粒体DNA演化的作用和重要性。我最近专注于在寿命调节中对线粒体的影响。我选择使用双壳类动物模型的比较方法。该模型包括地球上寿命最长的复杂动物物种，即山十个岛屿，可以达到507年。该记录是由冰岛人口的个人获得的。在北大西洋（欧洲和北美）的其他人群中，最大寿命在40年到200 - 300年之间变化。其他分类近的物种具有最大寿命，范围从几年到接近150年。因此，我可以使用二维比较模型：在广泛的最大寿命范围内（从4年到507年）内的不同物种的比较，并比较不同的A.岛化的不同种群，其特征是标准的最大寿命为35年至400年（参见Blier等人的细胞和发育生物学中的Blier等人，2017年）。我们先前观察到线粒体膜的鲁棒性与氧化物胁迫（表示为脂肪酸含量和过氧化指数）ROS管理与海洋双壳类中的最大寿命（Munro＆Blier，2012年）之间存在明确的联系。我们还证明，长寿命物种的线粒体产生的H2O2的外排比短寿命要低得多（Munro等人，2013年）。基于这些观察结果，我们将加深对线粒体结构与功能与动物寿命之间联系的分析。已经提出了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）调节凋亡诱导机制的减少2）ROS管理障碍3）电子传输系统（ETS）超复合物的不稳定性。我的学生，受训者和我将表征线粒体膜的精细结构（膜的脂质症分析：磷脂，立体声，心磷脂含量和结构）以及压力反应。