How mitochondrial physiology impacts protein sorting

线粒体是细胞能量的主要产生者。因此，线粒体生理学将影响许多不同的细胞通路并不出人意料。我的实验室主要研究的一个途径是蛋白质在内膜系统的隔室之间的运输，特别是内质网(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。我的实验室对调节参与内质网到高尔基体转运的蛋白质的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，它们从昆虫细胞中耗尽，导致运输和高尔基体形态表型。根据它们对高尔基体膜的影响，这些所谓的探戈蛋白可以分为几类。据报道，A类蛋白导致高尔基体膜被内质网吸收。到目前为止，探戈蛋白的功能仍然不清楚，有一种蛋白被证明影响从内质网到高尔基体的运输。然而，目前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。我们假设一些探戈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转运过程是如何调节的，特别是通过间接方法。我们对TANGO2蛋白进行了一些初步的研究，发现该蛋白可能定位于线粒体并影响线粒体的功能。然而，该蛋白的耗尽严重影响了内质网到高尔基体的运输。因此，该计划的目的是：目的1：阐明TANGO2的细胞定位及其影响因素。虽然初步研究表明TANGO2是一种线粒体定位的蛋白质，但这些需要得到证实，线粒体中的位置需要解决，其定位涉及的机制也需要解决。目的2：探讨TANGO2在线粒体动力学中的作用。初步研究表明，TANGO2在线粒体顶端附近富含，天然缺乏该蛋白的细胞有更多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对膜转运和线粒体生理的影响。关于TANGO2如何影响膜交通，可以提出几个假说。这些影响包括间接影响，如调节能量水平，调节在膜运输和高尔基形态中起作用的因子，以及在这一过程中更直接的影响。这些目标将是第一次阐明TANGO2的基本功能，并将提供第一项研究，以解决线粒体生理和蛋白质运输之间的联系。

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.