Discusses the mechanism by which the cell recycles its constituents and clears out protein aggregates.
Hard times exist for all life-forms. The population of any species grows exponentially until the amount of what it feeds on matches what is available to feed it. Anything that drops the amount available, depletion, drought, what have you, results in starvation, and thus episodes of starvation become inevitable. The ability to survive starvation must be developed and retained if a species is not to go quickly extinct.
Some species simply shut down for the duration and wait for the good times to return. Others draw on reserves built up in times of surplus. Humans have body fat as reserve for energy but have no comparable tissue dedicated to protein storage. Instead each cell must consume some part of itself to survive. Cells from yeast to humans have a complex mechanism to deal with the lean times called autophagy 6.
Cells form membrane-bound compartments within themselves for specific activities. One common compartment so formed is called the lysosome. It contains enzymes in an acid environment that can degrade lipids, carbohydrates, nucleic acids, and proteins and is where the cell recycles its degraded or surplus parts.
In chaperone-mediated autophagy as mentioned in an earlier chapter, chaperone proteins escort degraded proteins to the surface of the lysosome where protein complexes embedded in the its membrane transport them into the body of the lysosome for digestion.
Lysosomes also participate in two other forms of autophagy, microautophagy and macroautophagy that operate in bulk rather than one molecule at a time.
In microautophagy the membrane of the lysosome invaginates to suck in some portion of the cytoplasm around it including whatever might be floating in it. The pocket so formed then pinches off at its opening to form a new vesicle within the lysosome vesicle. The new vesicle and its contents are then digested. This process has even been seen to pinch off portions of the mitochondria and even of the nucleus109.
In macroautophagy the lysosome merges with another membrane-bound vesicle and releases its digestive enzymes into it. Among the candidates for merger may be a so-called autophagosome which is itself formed for just this purpose.
The autophagosome begins as an empty membrane-bound vesicle (of mysterious origins 7) that, like the lysosome itself in microautophagy, invaginates to enclose some portion of the cytoplasm and its contents forming a filled vesicle within an otherwise empty vesicle. ( Note that an autophageosome can be rather large and encompass entire organelles such as mitochondria and peroxisomes.) The empty vesicle is then filled by merger with lysosomes that then digest the internal vesicle.
The net effect of the two processes is the same, some bulk of the cytoplasm is selectively or non-selectively enclosed and its contents are recycled by lysosomes.
Note that micro-autophagy provides a means to recycle the lysosome membrane. How the internal enzymes of the lysosome get recycled is a bit of a mystery. Perhaps as they degrade, they lose their acid resistance and are then digested by their fellow enzymes. The ultimate fate of the entire aging lysosome is usually to merge back into the vesicle factory of the cell, the endoplasmic reticulum (ER), from which it likely came. The ER then dumps any undigested lysosome contents so received into the cytoplasm by a special mechanism known as ERAD and the proteins are then recycled by the usual pathways.
There is also some evidence that lysosomes can merge with the outer cell membrane as well (exocytosis) and dump their contents outside the cell 8. This may account for the extracellular plaques observed in AD.
And finally, perhaps sometimes an aged lysosome simply loses its acidity, shrivels and disintegrates.
Though also used by the cell for other purposes, non-selective bulk autophagy of the micro and macro varieties provides the mechanism for a cell to feed on itself in times of nutrient scarcity. Perhaps as a by-product it also clears out aggregates and other detritus that the other forms of cell trash removal miss. This is the very idea behind the protein cycling diet, to promote autophagy to reduce the aggregates that lead to neurological diseases and other lesser nuisances of aging. This might then explain why animals and people who have endured periods of famine have extended life spans compared to those who have not.
Macroautophagy is not entirely non-selective. There is evidence that degraded mitochondria and protein aggregates are actively transported to autophagosomes for engulfment and that their very presence can initiate autophagosome formation 9.