Unravelling the mechanistic basis of age-related mitochondrial membrane reorganizations in the ascomycete Podospora anserina

揭示子囊菌鹅足孢菌中与年龄相关的线粒体膜重组的机制基础

• 批准号: 283390074
• 负责人: Professor Dr. Heinz Dieter Osiewacz
• 金额: --
• 依托单位: Arbeitskreis Molekulare Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/283390074?language=en
• 关键词: Unravelling; mechanistic; basis; age; related

Mitochondria are eukaryotic cell organelles with a number of important functions (e.g ATP generation, biosynthesis of Fe/S clusters). Accordingly, functional impairments lead to degeneration, the development of different diseases and to biological aging. We use the filamentous ascomycete Podospora anserina as a well-established aging model with a strong mitochondrial etiology of aging. During aging of P. anserina gross reorganizations of the mitochondrial DNA and pronounced changes in mitochondrial morphology and ultrastructure occur. In the first period of the DFG-supported project we focused on the role of the mitochondrial F1Fo-ATP-synthase in shaping the ultrastructure of mitochondrial cristae. We experimentally validated a model which relies on earlier electron cryotomography data suggesting that the age-associated dissociation of F1Fo-ATP-synthase dimers, which are essential for the formation of cristae tips, is responsible for the transition of lamellar to vesicular mitochondria during aging. We demonstrated that ATP-synthase subunits e and g are involved in formation of typical cristae. We also showed that deletion of the gene coding for the subunit e induces bulk and mitochondrial autophagy (mitophagy) and thereby potentially compensates impairments caused by the ablation of the two F1Fo-ATP-synthase dimer assembly factors. In a second period of the project we now plan to concentrate on two main topics that will close existing gaps in the network of pathways involved in the biogenesis of mitochondria with most efficient functions. In the first subproject we will put special emphasis on the role of autophagy in strains with mitochondria which are impaired in F1Fo ATP-synthase dimer formation. The second subproject will investigate the role of MICOS (“mitochondrial contact site and cristae organizing system”), a macromolecular protein complex involved in the formation of cristae junctions. During the age-associated changes in mitochondrial ultrastructure MICOS needs to be remodeled. We first will analyze the composition of this complex in P. anserina and generate and analyze strains with modulated abundance (i.e. knockout and overexpression) of the two core subunits PaMIC10 and PaMIC60, respectively. Subsequently, we will experimentally analyze the role of MICOS in age-associated remodeling of the inner mitochondrial membrane. Both subprojects rely on a body of promising data and on experimental prerequisites elaborated in the first funding period. Overall, we will generate advanced new insights into components and mechanisms involved in the dynamic reorganization of mitochondria during aging of biological systems.

线粒体是真核细胞的细胞器，具有许多重要的功能（如ATP的产生，Fe/S簇的生物合成）。因此，功能障碍导致退化、不同疾病的发展和生物老化。我们使用丝状子囊菌Podospora anserina作为一个成熟的衰老模型，具有强大的线粒体衰老病因。在鹅绒委陵菜衰老过程中，线粒体DNA发生了大规模重组，线粒体的形态和超微结构发生了明显的变化。在DFG支持的项目的第一阶段，我们专注于线粒体F1 Fo-ATP合酶在塑造线粒体嵴的超微结构中的作用。我们通过实验验证了一个模型，该模型依赖于早期的电子cryotomography数据表明，年龄相关的解离F1 Fo-ATP合酶二聚体，这是必不可少的嵴尖的形成，是负责在老化过程中的层状囊泡线粒体的过渡。我们证明了ATP合酶亚基e和g参与了典型嵴的形成。我们还表明，删除编码亚基e的基因诱导大量和线粒体自噬（线粒体自噬），从而潜在地补偿由两个F1 Fo-ATP合酶二聚体组装因子的消融引起的损伤。在该项目的第二阶段，我们现在计划集中在两个主要课题，将关闭现有的差距，在网络的途径参与线粒体的生物合成最有效的功能。在第一个子项目中，我们将特别强调线粒体F1 Fo ATP合酶二聚体形成受损的菌株中自噬的作用。第二个分项目将研究MICOS（“线粒体接触位点和嵴组织系统”）的作用，这是一种参与嵴连接形成的大分子蛋白质复合物。在线粒体超微结构的年龄相关的变化过程中，MICOS需要重塑。我们首先将分析该复合物在鹅绒委陵菜中的组成，并分别产生和分析具有两个核心亚基PaMIC 10和PaMIC 60的调节丰度（即敲除和过表达）的菌株。随后，我们将通过实验分析MICOS在与年龄相关的线粒体内膜重塑中的作用。这两个次级项目都依赖于一系列有希望的数据和第一个供资期所阐述的实验性先决条件。总的来说，我们将产生先进的新见解的组件和机制参与动态重组线粒体在老化的生物系统。

项目成果

Disruption of the MICOS complex leads to an aberrant cristae structure and an unexpected, pronounced lifespan extension in Podospora anserina

• DOI: 10.1002/jcb.30278
• 发表时间: 2022-03
• 期刊: bioRxiv
• 作者: Verena Warnsmann;Lisa-Marie Marschall;Anja C Meeßen;Maike Wolters;Lea Schürmanns;Marion Basoglu;S. Eimer;H. Osiewacz