Scientists Uncover new Major Pathway Cells Use to rapidly repair Leaky Lysosomes

Good news! Amazing stuff!

"... Indeed, the frequency of this leakiness increases as a person ages and likely plays a role in aging-associated diseases such as neurodegenerative conditions. ...
Research had already established one way that cells repair leaky lysosomes. Previously, a collection of proteins known as the ESCRT machinery was found to patch up holes in the organelles’ membranes. ...

the two mechanisms have evolved to repair different types of damage, with the ESCRT complex mending small pores while the [new] PITT pathway repairs larger holes.

The new pathway may be performing most of the cell’s handywork. The researchers found that cells usually take around an hour to repair damaged lysosomes, but this healing requires up to 11 hours in cells lacking PI42KA. ...
The researchers plan to screen drugs for their ability to activate the pathway, starting with currently available drugs that could be repurposed. One intriguing lead is ginseng, a plant used in traditional Chinese medicine, the components of which appear to activate PI42KA ..."

From the abstract:

"Lysosomal dysfunction has been increasingly linked to disease and normal ageing. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function."

Scientists Uncover Major Pathway Cells Use to Mend Leaky Lysosomes | The Scientist Magazine® Damaged lysosomes are repaired by a lipid-based signaling pathway dubbed PITT that could be targeted to treat neurodegenerative disease, its discoverers say.

A phosphoinositide signalling pathway mediates rapid lysosomal repair (open access)

Fig. 1: An unbiased proteomic screen identifies PI4K2A-mediated PtdIns4P signalling in rapid lysosomal repair.