Identification of a Putative Mitochondrial Solute Carrier that Regulates Mitophagy

ABSTRACT Mitochondria are essential for cell health and survival. Understanding the quality control machinery that mitochondria employ to maintain a healthy network is critical for health and disease. Our lab recently showed the role that lipid transfer protein Vps13D plays a critical role in mitochondrial clearance by autophagy (mitophagy) in the Drosophila developing midgut. Vps13D has been implicated in human movement disorders, highlighting the importance of understanding how it controls this process. Importantly, we do not know what proteins Vps13D may be interacting with at the mitochondrial surface to facilitate mitophagy. I performed an RNAi screen against mitochondrial genes that were shown to physically interact with Vps13D in human cells. I discovered that Mtch, the fly homolog of MTCH2, phenocopies both mitochondrial and autophagic defects that Vps13D mutants display, including failure to clear mitochondria, autophagic cargoes like p62, and the autophagy protein Atg8a. I generated a null mutant for Mtch, which displays phenotypes similar to what is observed by Mtch knockdown with RNAi and Vps13D mutants. Importantly, Mtch mutant cells exhibit a robust decrease in Vps13D protein puncta. I plan to use this Mtch mutant to: (1) characterize the function of Mtch in mitophagy, (2) determine the relationship between Mtch and Vps13D in mitophagy, and (3) investigate the relationship between Mtch and known regulators of autophagy and mitophagy. These studies will advance the field by creating a better understanding of mitophagy, and will also provide a novel genetic pathway to study that could lead to targeted therapies to correct mitochondrial disorders.