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Mechanisms of exercise-induced mitophagy: a new avenue to drug discovery

Grant number: 18/18627-3
Support type:Scholarships abroad - Research
Effective date (Start): February 11, 2019
Effective date (End): February 10, 2020
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Julio Cesar Batista Ferreira
Host: Daria Mochly-Rosen
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Stanford University, United States  

Abstract

The health benefits of exercise have long been recognized. The importance of autophagy for this process is now also well-established. New research suggests that significant benefits from exercise depend on selective degradation of defective mitochondria through mitophagy, but the mechanisms connecting these processes are unknown. This project aims to fill this critical gap in our knowledge. We hypothesize that mitophagy in muscle cells is facilitated by exercise-induced mitochondrial fission. This form of enhanced mitophagy could help quickly weed out defective mitochondrial proteins, thus strengthening the efficiency of remaining mitochondria in muscle cells. We will test this with the following specific aims: 1. Determine how exercise induces mitochondrial fission. Our preliminary data show that exercise induces mitochondrial fission in C. elegans muscle cells. We will test whether mitochondrial fission is also induced by exercise in other organisms, such as mice, and investigate the possible roles of known triggers for mitochondrial fission, such as ATP- and calcium-dependent signaling pathways, along with other pathways that might be muscle specific. 2. Determine how exercise-induced fission promotes mitophagy. Our preliminary data suggests that exercise-induced fission corresponds with increased mitophagy. We will investigate causative connections between the fission and mitophagy machineries, focusing on specific protein interactions that were previously shown to affect these processes. 3. Determine how sorting of defective components in mitochondria affects exercise-induced mitophagy. Asymmetries introduced during mitochondrial fission can generate different membrane potentials between daughter mitochondria in model cell lines. Daughter mitochondria with reduced membrane potential are more susceptible to degradation by mitophagy. Using membrane potential dyes, we will test whether exercise-induced fission introduces differences between muscle cell mitochondria and we will track protein aggregates tagged with fluorescent proteins to determine whether exercise-induced fission promotes clearance of the aggregates through mitophagy. Each of our aims uses cultured cells, C. elegans and mice as increasingly complex model systems. This one-year period in Dr. Mochly-Rosen lab at Stanford will allow me to explore their expertise to bear on the question how exercise induces mitophagy. It is worth mentioning that Dr. Mochly-Rosen lab has become a worldwide reference in the mitochondrial dynamics and mitophagy field. Moreover, this multidisciplinary and collaborative approach will take full advantage of the complementary expertise of other 2 labs (Anne Brunet lab at Stanford, and Alex van der Bliek lab at UCLA) in order to accomplish this multipronged proposal within 1 year. Together the aims form a cohesive series of experiments focused on understanding the mechanistic connections between exercise and improved mitochondrial health with an emphasis on the central role of mitophagy in this process. The long-term goal of this project is to provide a sound basis for developing new drugs and treatment regimens, boosting the restorative value of exercise.RelevanceWe will investigate the cellular basis for health benefits from exercise, focusing on increased turnover of defective mitochondria in muscle cells. A better understanding of this process will allow for the development of new treatments that amplify the benefits of exercise.