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

Author information

Affiliations

  • 1. Department of Cell Biology, New York University School of Medicine, New York, NY10016.
      Authors
    • Liao Y 1
    • Tham DKL 1
    • Liang FX 1
    • Chang J 1
    • Wei Y 1
    • Sudhir PR 1
    • Sall J 1
    • Ren SJ 1
    • Rindler MJ 1
    • Sun TT 1, 9
    (10 authors)
  • 2. Research Unit, Hospital Joan XXIII, Institut de Investigacio Sanitaria Pere Virgili (IISPV), Universitat Rovira i Virgili, Tarragona 43007, Spain.
      Authors
    • Chicote JU 2
    • Garcia-España A 2
    (2 authors)
  • 3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
      Authors
    • Arnold LL 3
    • Cohen SM 3
    (2 authors)
  • 4. The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104.
      Authors
    • Hu CA 4
    (1 author)
  • 5. Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
      Authors
    • Romih R 5
    (1 author)
    • Show all (9)

ORCIDs linked to this article

Molecular Biology of the Cell, 02 Oct 2019, 30(24):2969-2984
https://doi.org/10.1091/mbc.e19-05-0284 PMID: 31577526 PMCID: PMC6857570

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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.

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Funding 

Funders who supported this work.

BLRD VA (1)

NCI NIH HHS (1)

NCRR NIH HHS (2)

NIDDK NIH HHS (3)

NIH HHS (1)