Mechanisms of mitophagy in tissue health and homeostasis

Project Summary/Abstract The long-term goal of our research program is to explore how mitophagy promotes tissue health. Mitochondria generate cellular energy, and a natural byproduct of executing this essential function is susceptibility to damage. A wide assortment of human diseases, including metabolic and neurodegenerative diseases, shares the pathological feature of improper accumulation of damaged mitochondria. Mitophagy, a type of mitochondrial quality control (MQC), degrades damaged mitochondria to prevent their inappropriate accumulation; and therefore, represents a critical mechanism required for the maintenance of tissue health. Most of our understanding of mitophagy comes from research performed in cell lines in culture, and thus, little is known about how the diverse mechanisms of mitophagy promote tissue health in intact organisms. Our lab seeks to address this knowledge gap by leveraging the genetic advantages offered by the model organism Drosophila melanogaster. We previously discovered that disrupting the ataxia-associated gene Vps13D results in severe perturbations in mitophagy such that mitochondria fated for mitophagy become stalled prior to degradation. These data have enabled us to elucidate molecular mediators of in vivo mitophagy in the fly, allowing us to generate unprecedented genetic tools and preliminary hypotheses that will facilitate a better understanding of the utilization of mitophagy in physiological contexts to support tissue function. In the next five years, we propose to generate genetic tools to effectively manipulate all known forms of mitophagy in fruit flies through engineering of the genes required to execute mitophagy: mitophagy adapter and receptor proteins. With these tools we will test the hypothesis that the two mechanistic forms of mitophagy degrade mitochondria with functionally distinctive objectives. We will test this hypothesis by individually investigating the physiological roles of the two forms of mitophagy in flies: ubiquitin-dependent mitophagy (in Research Direction #1) and receptor-dependent mitophagy (in Research Direction #2). In the third research direction, we will probe the relationship between these distinct forms of mitophagy to better understand how their interplay maintains tissue health and homeostasis. Overall, the information generated from this proposal will provide foundational knowledge on a critical cell biological process closely associated with human disease. In the future, this knowledge can be used to facilitate the development of mitophagy-targeting therapeutics that have the potential to treat diseases and conditions associated with mitophagy perturbations such as Parkinson’s Disease, diabetes, and ischemia-reperfusion injuries.