Molecular Cell and Cancer Biology
First Thesis Advisor
Eric H. Baehrecke
Vps13D, Pink1, Autophagy, Vmp1, Membrane Contacts, Mitophagy, Mitochondrial Dynamics
Autophagy is the delivery of cytoplasmic cargo to lysosomes for degradation. Defects in autophagy are responsible for various diseases, including neurodegenerative diseases and cancer. While studies in yeast have largely characterized autophagy in response to nutrient starvation, these elegant studies do not account for autophagy in other contexts, including selective autophagy of organelles. A previous screen identified Vps13D as a gene required for the autophagic removal of mitochondria, mitophagy. Vps13D is highly conserved and essential in animals, and Vps13d loss-of-function mutants have enlarged mitochondria and mitophagy deficiencies in both cell and animal models. However, the mechanism by which Vps13D regulates these processes has not been defined.
Here, I use mitochondrial clearance in the developing Drosophila intestine and fibroblasts from VPS13D mutant patients as experimental models to investigate the function of Vps13D. I discover that Vps13D is a regulator of ubiquitin and Atg8a/LC3/GABARAP localization around mitochondria. These functions are dependent on Pink1, a ubiquitin kinase, and the core autophagy machinery, respectively. Furthermore, Vps13D regulates mitochondria and endoplasmic reticulum (ER) contact sites downstream of Vmp1, a repressor of mitochondria and ER contact sites. I find that Marf, a mitochondria and ER tether and regulator of mitochondrial fusion, acts downstream of both Vmp1 and Vps13D. These findings explain the phenotypes in Vps13d mutants, as dysregulation of ubiquitin, Atg8a, and mitochondria and ER membrane contact sites impair regulation of both autophagy and mitochondria morphology.
Shen JL. (2021). Vps13D Is a Regulator of Pink1-Mediated Mitophagy and Membrane Contacts. GSBS Dissertations and Theses. https://doi.org/10.13028/2fqq-az86. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/1124
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Available for download on Saturday, April 02, 2022