How mitochondrial physiology impacts protein sorting

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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.