Mitophagy is a catabolic process by which dysfunctional mitochondria are selectively degraded through autophagy. Dysregulation of this pathway has been associated with a wide range of diseases, including neurodegenerative diseases, cancer, and metabolic disorders. Mitophagy can be triggered by different stimuli such as mitochondrial depolarization, reactive oxygen species (ROS), hypoxia and nutrient starvation. My lab is focusing on the identification and characterization of novel regulators of hypoxia-induced mitophagy. Using a combination of multi-omics approaches and imaging-based siRNA screens, we have recently identified genes and proteins that are differentially expressed in U2OS cells upon hypoxia compared to controls. Differentially expressed candidates containing a putative LC3-interacting region (LIR) was further analyzed for their binding to ATG8 proteins and for their role in mitophagy by siRNA-mediated depletion in various mitophagy reporter cells. Intriguingly, several candidates were required for hypoxia-induced mitophagy of both a matrix and an outer mitochondrial membrane (OMM) reporter, while other candidates were selective for either reporter. Current studies focus on mechanistic insight and pathophysiological relevance of selected candidates. In conclusion, we have identified novel regulators of hypoxia-induced mitophagy that could pave the way for the development of targeted therapies for mitochondrial dysfunction-associated diseases.