Final Report Summary - MITOPEXLYSONETWORK (Mitochondria, Peroxisomes and Lysosomes - the "menage a trois" of cellular metabolism) The organelles in a cell function as if they were different services in a city. They not only need to be there, they need to be in the right place and have the right connections, for them and the city to function appropriately. While for many years the organelles were studied separately, we started this project with the goal to determine if they were communicating, and how this communication was taking place. We found that not only they communicate with each other, but this communication is different if one of these organelles is not functioning well. And as in the city, when one part is not working well it can affect others, the same happens with organelles: primary defects in one, caused for example by genetic mutations, result in secondary perturbations in others. Some of the organelles that we have worked with are the mitochondria (which can be seen as the power plants of the city, as they generate most of the energy) and the lysosomes (which can be perceived as the recycling center, since they convert big components into smaller parts that can then be used to build something else). It has been observed in many diseases that when the recycling center is not working, the power plants become inneficient. Part of this is due to the inability to process trash, and therefore trash bags (which in cells would correspond to autophagosomes) are not picked up and delivered to the recycling center, thus clogging the streets and perturbing the function of the city. We found that there were multiple mechanisms by which the impaired recycling centers result in innefficient power plants, and we used that knowledge to fix the power plants. Secondly, we also tested why defects in the power plants affect the recycling center. We found that when there is an acute defect in the power plants, which implies that some parts of these plants need to be sent to be recycled, the recycling center goes into overdrive, working extra to help clean up. Also, the amount of garbage trucks that are available is increased, so that the damaged parts can be recycled faster. At the same time, new parts are made for the power plants, so that the system can go back to normal. However, if the problem in the power plant persists for too long, the city prefers to shut-down the recycling arm, and instead work with a damaged power plant - the alternative would be losing completely the power plant, which would have devastating consequences to that city - as it has to the cells in the human body.
