MP46-05 MITOCHONDRIA OF UROTHELIAL UMBRELLA CELLS PLAY A CENTRAL ROLE IN DETOXIFICATION TO REMOVE DYSFUNCTIONAL PROTEINS AND CERTAIN URINARY TOXINS: IMPLICATIONS IN MAJOR BLADDER DISEASES

Abstract

You have accessJournal of UrologyInfections/Inflammation/Cystic Disease of the Genitourinary Tract: Kidney & Bladder I (MP46)1 Apr 2020MP46-05 MITOCHONDRIA OF UROTHELIAL UMBRELLA CELLS PLAY A CENTRAL ROLE IN DETOXIFICATION TO REMOVE DYSFUNCTIONAL PROTEINS AND CERTAIN URINARY TOXINS: IMPLICATIONS IN MAJOR BLADDER DISEASES Yi Liao*, Daniel Tham, Feng-Xia Liang, Ellen Shapiro, Herbert Lepor, Xue-Ru Wu, and Tung-Tien Sun Yi Liao*Yi Liao* More articles by this author , Daniel ThamDaniel Tham More articles by this author , Feng-Xia LiangFeng-Xia Liang More articles by this author , Ellen ShapiroEllen Shapiro More articles by this author , Herbert LeporHerbert Lepor More articles by this author , Xue-Ru WuXue-Ru Wu More articles by this author , and Tung-Tien SunTung-Tien Sun More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000901.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Urothelium that covers much of the urinary tract has a very long (6 – 12 month) lifespan to serve as a constant permeability barrier, and as such, it must possess efficient mechanisms to handle cellular dysfunctional proteins and urinary toxins in order to stay healthy. Such “detoxification” mechanisms are particularly needed during urinary obstruction or infection when increased amounts of cell surface membranes are endocytosed for degradation or when urothelial cells are exposed to carcinogens. Despite their critical importance, these mechanisms have not been delineated. When analyzing a diverse array of mouse models lacking individual uroplakins or sorting nexin 31 or exposed to arsenite, we discovered a urothelial mitochondria-based detoxification mechanism that is functionally convergent from divergent causes and whose deficiency may play a major role in urothelial pathophysiology. METHODS: Urothelia of normal mice and knockout mice lacking sorting nexin 31 (Snx31), uroplakin II (UPII), UPIIIa or arsenite-treated mice were subjected to transmission electron microscopy and antibody staining for markers of ER, Golgi, mitochondria, lipid droplet, autophagy and apoptosis. RESULTS: The mitochondria of urothelial umbrella cells lacking Snx31, a major component of multivesicular body important for membrane degradation, accumulated massive amounts of inclusion bodies that were strongly positive for markers for lipid droplets (LDs). These LDs were also present in umbrella cells lacking UPII or UPIIIa, conditions causing disturbances in uroplakin assembly and excessive membrane degradation. Furthermore, LDs were found in umbrella cells of mice treated with arsenite, and this was accompanied by increased ER stress, autophagy and apoptosis. Finally, while less abundant, LDs were detected in normal umbrella cells, suggesting that they are operative normally at a low level but induced in pathological conditions. CONCLUSIONS: It is evident from our data that the mitochondria of umbrella cells are strongly induced to accumulate lipid droplets by diverse pathological conditions, and that this represents a functionally convergent mechanism for sequestration and degradation of urothelial membranes and certain urinary toxins. Our data, coupled with other recent reports showing similar mitochondrial LDs in umbrella cells deficient for PPAR-g or spinal cord injury-induced oxidative stress, suggest that mitochondrion is a principal detoxification organelle in urothelial umbrella cells and that antioxidants targeting mitochondria may help alleviate urothelial damages caused by mechanical stress, infection, inflammation, injury and urinary toxins. Source of Funding: NIH © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e674-e675 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yi Liao* More articles by this author Daniel Tham More articles by this author Feng-Xia Liang More articles by this author Ellen Shapiro More articles by this author Herbert Lepor More articles by this author Xue-Ru Wu More articles by this author Tung-Tien Sun More articles by this author Expand All Advertisement PDF downloadLoading ...