TY - JOUR
T1 - Mitochondrial lipid droplet formation as a detoxification mechanism to sequester and degrade excessive urothelial membranes
AU - Liao, Yi
AU - Tham, Daniel K.L.
AU - Liang, Feng Xia
AU - Chang, Jennifer
AU - Wei, Yuan
AU - Sudhir, Putty Reddy
AU - Sall, Joseph
AU - Ren, Sarah J.
AU - Chicote, Javier U.
AU - Arnold, Lora L.
AU - Hu, Chih Chi Andrew
AU - Romih, Rok
AU - Andrade, Leonardo R.
AU - Rindler, Michael J.
AU - Cohen, Samuel M.
AU - DeSalle, Rob
AU - Garcia-España, Antonio
AU - Ding, Mingxiao
AU - Wu, Xue Ru
AU - Sun, Tung Tien
PY - 2019/11/15
Y1 - 2019/11/15
N2 - The apical surface of the terminally differentiated mammalian urothelial umbrella cell is mechanically stable and highly impermeable, in part due to its coverage by urothelial plaques consisting of 2D crystals of uroplakin particles. The mechanism for regulating the uroplakin/plaque level is unclear. We found that genetic ablation of the highly tissue-specific sorting nexin Snx31, which localizes to plaques lining the multivesicular bodies (MVBs) in urothelial umbrella cells, abolishes MVBs suggesting that Snx31 plays a role in stabilizing the MVB-associated plaques by allowing them to achieve a greater curvature. Strikingly, Snx31 ablation also induces a massive accumulation of uroplakin-containing mitochondria-derived lipid droplets (LDs), which mediate uroplakin degradation via autophagy/ lipophagy, leading to the loss of apical and fusiform vesicle plaques. These results suggest that MVBs play an active role in suppressing the excessive/wasteful endocytic degradation of uroplakins. Failure of this suppression mechanism triggers the formation of mitochondrial LDs so that excessive uroplakin membranes can be sequestered and degraded. Because mitochondrial LD formation, which occurs at a low level in normal urothelium, can also be induced by disturbance in uroplakin polymerization due to individual uroplakin knockout and by arsenite, a bladder carcinogen, this pathway may represent an inducible, versatile urothelial detoxification mechanism.
AB - The apical surface of the terminally differentiated mammalian urothelial umbrella cell is mechanically stable and highly impermeable, in part due to its coverage by urothelial plaques consisting of 2D crystals of uroplakin particles. The mechanism for regulating the uroplakin/plaque level is unclear. We found that genetic ablation of the highly tissue-specific sorting nexin Snx31, which localizes to plaques lining the multivesicular bodies (MVBs) in urothelial umbrella cells, abolishes MVBs suggesting that Snx31 plays a role in stabilizing the MVB-associated plaques by allowing them to achieve a greater curvature. Strikingly, Snx31 ablation also induces a massive accumulation of uroplakin-containing mitochondria-derived lipid droplets (LDs), which mediate uroplakin degradation via autophagy/ lipophagy, leading to the loss of apical and fusiform vesicle plaques. These results suggest that MVBs play an active role in suppressing the excessive/wasteful endocytic degradation of uroplakins. Failure of this suppression mechanism triggers the formation of mitochondrial LDs so that excessive uroplakin membranes can be sequestered and degraded. Because mitochondrial LD formation, which occurs at a low level in normal urothelium, can also be induced by disturbance in uroplakin polymerization due to individual uroplakin knockout and by arsenite, a bladder carcinogen, this pathway may represent an inducible, versatile urothelial detoxification mechanism.
UR - http://www.scopus.com/inward/record.url?scp=85075094268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075094268&partnerID=8YFLogxK
U2 - 10.1091/mbc.E19-05-0284
DO - 10.1091/mbc.E19-05-0284
M3 - Article
C2 - 31577526
AN - SCOPUS:85075094268
VL - 30
SP - 2969
EP - 2984
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 24
ER -