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

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.

Implications of lipid droplets in lung cancer: Associations with drug resistance (Review)

“…The lipid droplets coated with the inner nuclear membrane are then released into the nucleus, the coated nuclear membrane breaks and then the encapsulated lipid droplets are released (51). Recent findings suggest that lipid droplets are also produced inside the mitochondria (52) (Fig. 1B).…”

“…1B). After knocking out tissue-specific sorting nexin Snx31 in urothelial umbrella cells, multivesicular bodies (MVBs) were no longer observed and lipid droplets were produced inside the mitochondria, which were further degraded by autophagy (52). This result suggests that mitochondria also have lipogenic activity.…”

Challenges Facing an EM Core Laboratory: Mitochondria Structural Preservation and 3DEM Data Presentation

“…Recent developments in chimeric antigen receptor (CAR) T-cell immunotherapy have added a new weapon in the fight against cancer. Mitochondria are metabolic organelles that actively transform their ultrastructure as the cells become involved in different phases of antiviral responses and/or cell death, and mitochondrial remodeling is a signaling mechanism that instructs T-cell metabolic programming [20]. Mitochondrial changes in T-cells of cancer models are an important aspect for cancer research.…”

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“…Actually, lipid droplets are able to tune cell oxidative stress [ 99 ]. According to some authors, lipid droplets have the main property to buffer and modulate the delayed release of fats, both as signaling molecules and metabolic sources, and the delayed release is fundamental for many purposes, such as energy and redox homeostasis, tuning of autophagy [ 100 ] and of the ER stress [ 99 ]. In this sense, lipids actively participate as mediators in the cross talk between cells and tissues.…”