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.

Anti-Aging Clues Lurk in Lysosomes, the Recycling Centers of the Cell

Amazing stuff! Are you ready for a longer life? How will longevity affect world human population?

"... that molecules produced during the recycling process can also serve as signals that talk to other parts of the body. 

These signals seem to play a role in determining how and when organisms grow old. ... have found evidence that the anti-aging messages are transmitted between cells too, and among different tissues ... The results suggest that lysosome signals help coordinate the body’s aging process – and prolong the lives of some organisms. ...
discovered that when lysosomes produce a fatty acid called dihomo-gamma-linoleic acid, it triggers a chain reaction of cellular messages that ultimately extend the worms’ lives. When the researchers dialed up this fatty acid signaling, worms lived 20 to 25 days, an increase from the normal lifespan of 17 days. Crucially, the signal molecule was generated in fat tissues, yet detected by neurons elsewhere in the worms. That means lysosomes produce signals that cells use to coordinate longevity across different tissues. ..."

From the abstract:

"Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in aging-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate aging remains unclear. Here, we report a fat-to-neuron lipid signaling pathway induced by lysosomal metabolism and its longevity promoting role in Caenorhabditis elegans. We discovered that lysosomal lipolysis in peripheral fat storage tissue up-regulates the neuropeptide signaling pathway in the nervous system to promote longevity. ... Together, these results reveal lysosomes as a signaling hub to coordinate metabolism and aging, and a lysosomal signaling mechanism that mediates intertissue communication to promote longevity."

Anti-Aging Clues Lurk in Lysosomes, the Recycling Centers of the Cell | HHMI Scientists have discovered that lysosomes in roundworms produce molecules that allow cells to ‘talk’ to one another about aging, coordinating the process across the entire organism.

Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity (open access, but this is the 2021 preprint version)

Is It Time to Rethink Parkinson's Pathology?

Very recommendable survey article about Parkinson's! Good news! I would guess, Parkinson's will be defeated within the next 10 years or so!

It appears researchers are now more focusing on brain cells' waste management to find the cause. The article discusses e.g. lysosomal dysfunction, mitochondrial dysfunction and how mitochondria and lysosomes interact.

Is It Time to Rethink Parkinson's Pathology? | The Scientist Magazine®: New evidence points to a waste-clearing problem in patients' cells, rather than the accumulation of protein tangles, as the root cause of the neurodegenerative disease.