How mitochondrial physiology impacts protein sorting

线粒体是细胞能量的主要来源。因此，线粒体生理会影响许多不同的细胞通路并不意外。我的实验室主要研究的一个途径是蛋白质在膜系统各隔室之间的运输，特别关注内质网（ER）和高尔基体之间的运输。奇怪的是，线粒体健康和这一基本细胞过程之间的关系还没有得到很好的研究，尽管人们可以预期会有影响。我的实验室对调节内质网到高尔基转运过程中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失导致了运输和高尔基形态表型。这些所谓的TANGO蛋白根据其对高尔基膜的作用分为几类。据报道，A类蛋白可使高尔基体膜被内质网吸收。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内质网到高尔基体的运输。然而，尚不清楚是否所有这些蛋白质都直接影响内质网到高尔基体的转运。我们假设一些TANGO蛋白会间接影响这一过程。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。我们对TANGO2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，这种蛋白质的消耗对内质网到高尔基体的运输有严重影响。因此，本项目的目的是：目的1：阐明TANGO2的细胞定位及其影响其定位的因素。虽然初步研究表明TANGO2是一种线粒体定位蛋白，但这些有待证实，其在线粒体内的位置及其定位机制需要解决。目的2：评估TANGO2在线粒体动力学中的作用。初步研究表明，TANGO2在线粒体尖端附近富集，而自然缺乏这种蛋白质的细胞有更多的较短的、未分枝的线粒体。这表明TANGO2参与了线粒体融合。目的3：了解TANGO2如何影响膜交通和线粒体生理。关于TANGO2如何影响膜交通，可以提出几种假设。这些包括间接影响，如能量水平的调节，在膜交通和高尔基形态中起作用的因子的调节，以及在这一过程中更直接的影响。这些目标将是第一个阐明TANGO2的基本功能，并将提供第一个解决线粒体生理学和蛋白质运输之间联系的研究。

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.