Investigating Polycystin‐2‐mediated mitophagy as a stress response through its role in NAFLD

Abstract

Non‐alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, is characterized by aberrant dysregulation of cellular energy mechanisms, including defective autophagy and mitochondrial function. Inhibiting general autophagy in models of NAFLD has produced contradictory results, resulting in both protection against and causation of hepatic steatosis and insulin resistance. However, the specific role of autophagy to selectively degrade mitochondria—the process known as mitophagy—has not been studied in the context of NAFLD development. The main goals of this project are to establish the function of dysregulated mitophagy in the development of NAFLD, and to determine how Polycystin‐2 (PC2), a Ca2+‐modulating protein on the endoplasmic reticulum (ER) membrane, works to promote hyper‐activation of mitophagy through its interaction with Bcl‐2 associated athanogene 2 (BAG2). My interest in PC2 and BAG2 is based on published and preliminary data demonstrating 1) increased PC2 and BAG2 expression in human and murine livers with NAFLD, 2) BAG2 as an interacting partner of PC2 that promotes PTEN‐induced putative kinase 1 (PINK1)‐mediated mitophagy following PC2 up‐regulation, and 3) protection against insulin resistance and hepatic steatosis in PC2 haploinsufficient mice fed a high fat diet (HFD). In this work, I examine how PC2 is up‐regulated under stress to modulate mitophagy and mitochondrial function, as well as how PC2‐null hepatocytes respond to HFD‐induced NAFLD, and determine how observed mitochondrial morphological and functional alterations that occur in hepatocytes following the onset of NAFLD are altered by PC2 and BAG2. These results will confirm PC2 as a stress response protein capable of regulating mitophagy, and will help resolve the role of dysregulated autophagy in NAFLD development.Support or Funding InformationFunding provided by T32GM007324 and F31DK118836.