A Look at Lysosomal Exocytosis, or Throwing the Garbage Out

Lysosomes are one type of recycling unit in the cell, responsible for breaking down damaged cellular components and some unwanted proteins. One of the causes of aging is that in long-lived cells types of metabolic waste that cannot be broken down accumulate in lysosomes. These compounds are collectively called lipofuscin, and their presence in large amounts renders lysosomes bloated and inefficient. Cellular housekeeping as a whole then deteriorates until cells die or fall into dysfunctional states that harm tissue function. Everyone has this to look forward to. There is much less work taking place on a solution to this issue than on the analogous problem of lyososmal storage diseases, however, a collection of rare genetic disorders in which the lysosome lacks some of the tools it needs to break down ordinary, common structures and unwanted molecules. These compounds build up inside the cell and it eventually dies. If you follow the field of aging research you will see this over and and again: the harms that happen to everyone at the end of life are largely ignored, but there is much more interest in tackling similar problems that happen to just a few people in younger years.

Researchers here are looking at lysosomal exocytosis, which is a fancy term for the process in which a lysosome docks at the interior of the cell surface and then throws its cargo of garbage outside the cell. The degree to which this normally happens can be increased greatly, and early indications are that this is a potentially beneficial approach to treating lysosomal storage diseases. Will this be useful in the lysosomal issues that accompany aging, however? The type of garbage at issue is totally different, and it may well be that this would just swap the one problem for another. We have no idea what large amounts of lipofuscin between long-lived cells in nerve tissue will do over the long-term, though this is certainly something that could be investigated. Overall I'd prefer the SENS approach of infusing the body with enzymes that can safely break down lipofuscin constituents, but all of these strategies are at least worth investigation.

Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane trafficking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions.

A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we first discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We then discuss whether lysosomal exocytosis can be manipulated to correct lysosomal and cellular dysfunction caused by excessive lipid storage, providing a potentially general therapeutic approach for LSDs.

Link: http://dx.doi.org/10.1194/jlr.R046896


I'm a great enthusiast of the SENS approach, but you can only introduce so many novel lysosomal enzymes. My impression of lipofuscin is that there are a few common constituents, amenable to targeted remediation via the SENS approach, and a greater number of uncommon constituents that are even more recalcitrant. These heterogeneous and highly-disordered waste products would likely require either exocytosis followed by excretion or an in-situ degredation process even more sophisticated than enzymes, such as nano-machines. Such a therapy may not be necessary for "first generation" SENS, however. It may be good enough for 30 extra years just to round up the usual suspects.

Posted by: José at July 6th, 2014 9:15 AM

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