Mitochondrial lipid droplet formation as a detoxification mechanism to sequester and degrade excessive urothelial membranes

Yi Liao, Daniel K.L. Tham, Feng Xia Liang, Jennifer Chang, Yuan Wei, Putty Reddy Sudhir, Joseph Sall, Sarah J. Ren, Javier U. Chicote, Lora L. Arnold, Chih Chi Andrew Hu, Rok Romih, Leonardo R. Andrade, Michael J. Rindler, Samuel M. Cohen, Rob DeSalle, Antonio Garcia-España, Mingxiao Ding, Xue Ru Wu, Tung Tien Sun

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2969-2984
Number of pages16
JournalMolecular biology of the cell
Volume30
Issue number24
DOIs
StatePublished - Nov 15 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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