Processing of Damaged Lysosomes: a Potential Target for Slowing Aging

Lysosomes are membrane-bound packages of enzymes that act as the cell’s waste disposal system, and play a role in a variety of other cellular processes. Lysosome dysfunction has emerged as a factor in age related diseases, as these organelles slowly accumulate damage over time, causing them to leak, damaging the cell and triggering inflammatory pathways.

Cells are able to repair damaged lysosomes, or destroy them in a process called lysophagy. Improving our understanding of the mechanisms involved, and how the decision between repair and lysophagy is made, should further our understanding of age-related disease, eventually offering new avenues to increase healthy lifespan.

Since the discovery of lysophagy as a mechanism to dispose damaged lysosomes, major progress has been made with regard to its regulation. Clearly, we now need to identify the full ubiquitination machinery which likely involves diverse ubiquitin ligases, and put together a full catalog of the proteins ubiquitinated during the endolysosomal damage response. Moreover, we need to clarify the function of p97 in the process and identify its targets on the lysosome. Given the recent identification of a lysosome repair pathway, we need to understand the basis for decision making between repair and terminal clearance of affected lysosomes. Much process has been made regarding autophagy of membrane-rupturing bacteria. We need to clarify how much of the mechanisms apply to sterile damage, for example, in neurodegeneration or other diseases. In this context, it is crucial to clarify to what extent lysosomal damage (and ELDR) contributes to neurodegeneration, spreading of neurotoxic aggregation and problems associated with lysosomal storage diseases. Lastly, it will be important to clarify whether lysophagy is also a means to adjust the amount of intact lysosomes and adapt it to cellular needs, as has been shown for other organelles.

Papadopoulos, C., Kravic, B., & Meyer, H. (2020). Repair or Lysophagy: Dealing with Damaged Lysosomes. Journal Of Molecular Biology, 432(1), 231-239. doi: 10.1016/j.jmb.2019.08.010