How mitochondrial physiology impacts protein sorting

线粒体生理学如何影响蛋白质分选

• 批准号: RGPIN-2020-04613
• 负责人: Sacher, Michael
• 金额: $ 3.06万
• 依托单位: Concordia 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=745874
• 关键词: How; mitochondrial; physiology; impacts; protein

The mitochondria are the main produces of cellular energy. Therefore, it is not unexpected that mitochondrial physiology will affect many different cellular pathways. One pathway that is a main focus of study in my laboratory is the transport of proteins between compartments of the endomembrane system, with a particular focus on transport between the endoplasmic reticulum (ER) and the Golgi. Curiously, the relationship between mitochondrial health and this fundamental cellular process has not been well studied, though one can expect there to be an effect. My laboratory has become increasingly interested in factors that regulate the function of proteins involved in ER-to-Golgi transport. Work nearly 15 years ago by the Perrimon and Malhotra laboratories identified 20 proteins whose depletion from insect cells resulted in transport and Golgi morphological phenotypes. These so-called TANGO proteins fell into several classes depending on their affect on Golgi membranes. Class A proteins were reported to cause the Golgi membranes to be absorbed by the ER. To date, the functions of the TANGO proteins remain obscure with one being demonstrated to affect the transport from the ER to the Golgi. However, it is not known if all of these proteins directly affect ER-to-Golgi transport. We hypothesize that some of the TANGO proteins will indirectly affect this process. Thus the long-term goal of this work is to understand how membrane transport processes are regulated, particularly by indirect methods. We have performed some preliminary studies on the TANGO2 protein and find that this protein likely localizes to and affects the function of mitochondria. Yet depletion of this protein had severe effects on ER-to-Golgi transport. Therefore, the aims of this program are to: AIM 1: Elucidation of the cellular location of TANGO2 and the factors that influence its location. Although preliminary studies suggest that TANGO2 is a mitochondrially-localized protein, these need to be confirmed, the location within the mitochondria needs to be addressed as does the mechanism involved in its localization. AIM 2: Assess the role that TANGO2 plays in mitochondrial dynamics. Preliminary studies suggest that TANGO2 is enriched near the tips of mitochondria and that cells that are naturally devoid of the protein have a higher number of shorter, unbranched mitochondria. This suggests that TANGO2 is involved in mitochondrial fusion. AIM 3: Understand how TANGO2 affects membrane traffic and mitochondrial physiology. Several hypotheses can be suggested as to how TANGO2 affects membrane traffic. These include indirect effects such as regulation of energy levels, the regulation of a factor that functions in both membrane traffic and Golgi morphology, as well as more direct effects in this process. These aims will be the first to elucidate the basic functions of TANGO2 and will provide the first study to address the link between mitochondrial physiology and protein transport.

线粒体是细胞能量的主要生产者。因此，线粒体生理学将影响许多不同的细胞途径并不意外。在我的实验室研究的一个主要焦点是蛋白质在内膜系统的隔室之间的运输，特别关注内质网（ER）和高尔基体之间的运输。奇怪的是，线粒体健康与这一基本细胞过程之间的关系尚未得到很好的研究，尽管人们可以预期会有影响。我的实验室对调节ER到高尔基体转运蛋白质功能的因素越来越感兴趣。近15年前，Perrimon和Malhotra实验室的工作确定了20种蛋白质，这些蛋白质从昆虫细胞中消耗导致运输和高尔基体形态表型。这些所谓的TANGO蛋白根据它们对高尔基体膜的影响分为几类。据报道，A类蛋白导致高尔基体膜被ER吸收。迄今为止，TANGO蛋白的功能仍然不清楚，其中一种被证明影响从ER到高尔基体的转运。然而，目前尚不清楚是否所有这些蛋白质都直接影响ER到高尔基体的转运。我们推测，一些TANGO蛋白将间接影响这一过程。因此，这项工作的长期目标是了解膜运输过程是如何调节的，特别是通过间接方法。我们已经对TANGO 2蛋白进行了一些初步研究，发现该蛋白可能定位于线粒体并影响线粒体的功能。然而，这种蛋白质的耗尽有严重的影响ER到高尔基体的运输。因此，该计划的目的是：目的1：阐明TANGO 2的细胞定位和影响其定位的因素。虽然初步研究表明TANGO 2是一种神经定位蛋白，但这些需要得到证实，线粒体内的位置需要解决，其定位机制也需要解决。目的2：评估TANGO 2在线粒体动力学中的作用。初步研究表明，TANGO 2在线粒体的尖端附近富集，并且天然缺乏该蛋白质的细胞具有更高数量的较短，无分支的线粒体。这表明TANGO2参与线粒体融合。目的3：了解TANGO2如何影响膜运输和线粒体生理。关于TANGO2如何影响膜交通，可以提出几种假设。这些包括间接的影响，如调节能量水平，调节一个因素，在膜交通和高尔基体形态，以及在这个过程中更直接的影响。这些目标将首次阐明TANGO2的基本功能，并将首次研究线粒体生理学和蛋白质转运之间的联系。