Pathological molecular mechanisms underlying APOPT1 loss of function

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Mitochondria are fundamental organelles, responsible for extracting energy from food to warrant normal function to virtually all cells in the body, except for mature red blood cells which lack mitochondria. Mitochondrial disorders (MD) are a group of rare diseases caused by defective mitochondria. Mitochondria are made up of many proteins that are synthesized both inside the organelles, from genes contained in the mitochondrial genome, and outside, in the cytoplasm, from genes contained in the nucleus, whose proteins are then imported into the organelle. Malfunction of any of these proteins caused by mutations in the encoding DNA genes can cause a MD. These genetic diseases can involve any organ of the body, although the most commonly affected ones are the brain and muscle. A frequent observation in some people suffering from MD is the appearance or worsening of their neurological and/or muscular symptoms after metabolic stress caused by an infection with fever. The reasons why this happens are not clear and preventing the subsequent deterioration becomes an important medical challenge. The purpose of this project is to study the function of a protein that has been identified as a strong candidate to protect mitochondria from stress. Genetic mutations that prevent the formation of this protein have been found in a group of MD patients whose clinical course worsens after febrile episodes. First, we will study how the protein works inside the mitochondria and how it responds to oxidative stress as well as the mechanisms by which it is able to protect mitochondria from stress. Second, we will use cells from patients and fruit fly models devoid of the putative ‘stress-protecting’ protein, to study the effects of oxidative and heat-shock stresses on these models. This will let us understand what happens in the mutant cells during illnessrelated stress to eventually develop treatments aimed at preserving acceptable health conditions in people suffering from MD.