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. 2022 Oct;12(10):e1097.
doi: 10.1002/ctm2.1097.

The PITT pathway: Keeping lysosomes young

Haoxiang Yang  1 , Jay Xiaojun Tan  1   2
Affiliations

The PITT pathway: Keeping lysosomes young

Haoxiang Yang et al. Clin Transl Med. 2022 Oct.
No abstract available

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Fixing old lysosomes: The PITT pathway to the rescue. The phosphoinositide‐initiated membrane tethering and lipid transport (PITT) pathway is essential for rapid lysosomal repair. It is activated by multiple distinct, disease‐related lysosome‐damaging conditions, suggesting that it is a common mechanism for lysosomal quality control. The PITT pathway starts with robust lysosomal recruitment of PI4K2A, an enzyme that produces large amounts of the lipid messenger phosphatidylinositol‐4‐phosphate (PI4P) on damaged lysosomes. PI4P drives the formation of extensive, new membrane contact sites (MSCs) between the endoplasmic reticulum (ER) and damaged lysosomes by recruiting four oxysterol‐binding protein (OSBP)‐related protein (ORP) family members. OSBP and ORPs subsequently exchange lysosomal PI4P into cholesterol and phosphatidylserine (PS), respectively. Cholesterol by itself protects lysosomal membrane, and lysosomal PS activates autophagy protein 2 (ATG2)‐mediated lipid transfer for direct membrane repair. Loss of the PITT pathway due to deletion of PI4K2A is known to cause neurodegeneration and pre‐mature aging in both mice and human patients. TFEB or PITT activators are expected to improve lysosomal quality and activity, and thus may benefit human health, promoting healthy aging and alleviating age‐ and lysosome‐related diseases. Figure created with BioRender.com
See this image and copyright information in PMC

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