Tissue-specific roles of mitochondrial dynamics in stress resistance and longevity

线粒体动力学在抗应激和长寿中的组织特异性作用

• 批准号: RGPIN-2019-04302
• 负责人: VanRaamsdonk, Jeremy
• 金额: $ 2.7万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761364
• 关键词: Tissue; specific; roles; mitochondrial; dynamics

Mitochondria are a part of the cell that is responsible for the production of energy. Mitochondria also perform several other critical functions within the cell and are essential for life in most organisms. While mitochondria have been shown to influence aging, the relationship between mitochondrial shape, mitochondrial function and longevity is poorly defined. Under normal conditions, mitochondria are dynamic organelles: they continuously split off of larger mitochondrial networks, in a process known as mitochondrial fission, and rejoin those networks, in a process known as mitochondrial fusion. Combined these processes are known as mitochondrial dynamics. Experiments in a genetic model organism called C. elegans have shown that decreasing mitochondrial fission can lead to increased lifespan. Since similar observations have been made in yeast, and decreased mitochondrial fragmentation has been associated with longevity in long-lived human centenarians, this suggests that altering mitochondrial shape in order to form larger mitochondrial networks can increase longevity, and that this response is conserved across species. Currently, the mechanism by which altering mitochondrial dynamics can influence longevity is not known. Furthermore, the role of mitochondrial dynamics in an organism's response to stress, and how this might contribute to lifespan, is incompletely defined. We hypothesize that decreasing mitochondrial fragmentation increases lifespan through alterations in mitochondrial function. We further hypothesize that increasing an organism's capacity for fission and fusion through the simultaneous overexpression of fission and fusion proteins will increase mitochondrial health and longevity. To test these hypotheses, we will use C. elegans models to define the contribution of mitochondrial dynamics to stress resistance and longevity through the completion of two research projects. In Project 1, we will determine how different types of stress affect mitochondrial shape and how changing mitochondrial shape affects stress resistance. In Project 2, we will also define the conditions under which changes in mitochondrial dynamics can increase lifespan and explore the underlying mechanisms. By using C. elegans, we are able to examine mitochondrial morphology in a live animal, and to study the effect of modulating mitochondrial dynamics on whole organism phenotypes such as stress resistance and lifespan. Defining the relationship between mitochondrial dynamics, stress resistance and longevity, and elucidating the underlying mechanisms, will advance our knowledge about the role of mitochondrial morphology and function in aging and resistance to stress. Overall this work will increase our understanding of the aging process.

线粒体是细胞的一部分，负责产生能量。线粒体还在细胞内执行其他几个关键功能，并且是大多数生物体中生命所必需的。虽然线粒体已被证明会影响衰老，但线粒体形状，线粒体功能和寿命之间的关系尚不清楚。在正常情况下，线粒体是动态的细胞器：它们在称为线粒体分裂的过程中不断地从较大的线粒体网络中分裂出来，并在称为线粒体融合的过程中重新加入这些网络。结合这些过程被称为线粒体动力学。 在一种名为C.线虫已经表明减少线粒体分裂可以导致寿命延长。由于在酵母中也进行了类似的观察，并且线粒体碎片减少与长寿的人类百岁老人的寿命有关，这表明改变线粒体形状以形成更大的线粒体网络可以增加寿命，并且这种反应在物种中是保守的。目前，改变线粒体动力学可以影响寿命的机制尚不清楚。此外，线粒体动力学在生物体对压力的反应中的作用，以及这如何有助于寿命，还没有完全确定。我们推测，减少线粒体碎片增加寿命通过改变线粒体功能。我们进一步假设，通过同时过表达裂变和融合蛋白来增加生物体的裂变和融合能力将增加线粒体的健康和寿命。为了验证这些假设，我们将使用C。通过完成两个研究项目，建立了线虫模型，以确定线粒体动力学对抗逆性和寿命的贡献。在项目1中，我们将确定不同类型的压力如何影响线粒体形状，以及线粒体形状的变化如何影响应激抵抗力。在项目2中，我们还将定义线粒体动力学变化可以增加寿命的条件，并探索潜在的机制。利用C.通过对线虫的研究，我们能够检查活体动物中的线粒体形态，并研究调节线粒体动力学对整个生物体表型（如应激抗性和寿命）的影响。确定线粒体动力学，抗应激和长寿之间的关系，并阐明潜在的机制，将推进我们对线粒体形态和功能在衰老和抗应激中的作用的认识。总的来说，这项工作将增加我们对衰老过程的理解。