Re: Why don't lysosomes digest themselves??

Dear Julya,

You can imagine that the lysosome’s destructive environment would make 
quick work of anything, including itself and the cell that contains it.  
It is remarkable that the lysosome remains intact and, though I’m not 
aware of a complete explanation for this, I can tell you about a couple 
ideas that are floating around in scientists’ minds.

First, let’s review what you probably know already.  A lysosome is an 
organelle that is responsible for breaking down big molecules.  These 
molecules can come from outside or inside the cell, and can be parts of 
microbes that the cell must kill to protect itself.  If you look at all 
the lysosomes in a cell, you find that their shapes can be quite diverse.  
This may be reflective of several kinds of lysosomes, each suited for a 
particular role: extracting nutrients from things the cell has absorbed, 
killing microorganisms, or breaking down debris.  These various organelles 
are defined as lysosomes because they all have a high concentration of 
enzymes known as acid hydrolases—“hydrolases” because they hydrolyze, or 
break apart, other things and “acid” because they require a low-pH 
environment for optimal function.  These acid hydrolases include 
nucleases, which target nucleic acids like those in DNA and RNA; 
proteases, which target proteins, glycosidases, which target sugars; and 
lipases, which target lipids.  

Remember that enzymes are characterized by “substrate specificity,” which 
means that they can only act on molecules of a certain shape (a shape that 
fits that enzyme’s active zone).  This is our first clue to how lysosomes 
can protect themselves from their own enzymes—if the enzymes can’t fit 
lysosome parts into their active zones, then those lysosome parts are 
safe.  In fact, it is known that proteins in the lysosome membrane have an 
uncommonly large number of sugar molecules stuck to them.  These sugars 
act as a shield, keeping many acid hydrolases from segments of protein 
that they would otherwise recognize and chop up.  The process of adding 
sugars to other things is called “glycosylation,” and a protein with 
sugars on it is said to be a “glycoprotein.”  Of course, the lysosome 
contains glycosidases as well, and so those protein shields probably don’t 
last forever.

This imperfect protection of a lysosome’s parts may actually be good for 
the cell.  If the lysosome has evolved ways to protect itself from its 
enzymes, then it is likely that microbes can evolve those same 
mechanisms.  It is to the lysosome’s advantage to have enough safeguards 
to keep itself intact for a reasonable amount of time, but not so many 
that pathogens can hijack those safeguards to their own cell-killing 
purposes.  Furthermore, anything the cell makes lysosome-proof will 
probably end up accumulating in lysosomes, where it takes up precious 
space and cannot be recycled for other cellular processes.  Thus, if it 
means that lysosomes get the ability to destroy many things, it is okay if 
they damage themselves in the process.  What matters is how fast they do 
so; if it isn’t too fast, then the cell can replace or repair the damage 
and keep the lysosome intact.  You then get the best of both worlds: a 
lysosome that can chew up a wide variety of things but that also stays in 
one piece.  

What happens if the lysosome ruptures?  It appears as if the lysosomal 
contents would wreak havoc.  In actuality, the cell is protected by the 
neutral pH of its cytoplasm.  Without an acidic environment, the acid 
hydrolases are inhibited such that their threat to the cell is minimized.  
The pH of cytoplasm is 7.2, while that of lysosomes is around 5.  Because 
pH is on a logarithmic scale, there are more than two orders of magnitude 
between the ideal environment for acid hydrolases and the intracellular 
environment—this is a reasonable margin of safety.

In summary, lysosomes must maintain a balance between destroying 
themselves and being ineffective at digesting many molecules.  They 
probably protect themselves just enough to buy time for maintenance by 
other cellular processes.  It would be very interesting to identify the 
various proteins, lipids, and sugars in the lysosome membrane, identify 
the targets of the acid hydrolases, and then see how much those two groups 
overlap.  One could then get an idea of how much of the lysosome is prone 
to self-digestion.  It would also be interesting to know what various 
bacteria have evolved to protect themselves from lysosomes, and then see 
if these bacterial defenses are copies of devices lysosomes use to extend 
their own lifespan.

Most of this information was taken from Molecular Biology of the Cell, an 
excellent textbook written by Bruce Alberts and colleagues.

Best,

Michael