New insight into the cellular recycling factories

Lysosomes are the major players in cellular waste disposal. Analyzes are now revealing that these tiny degradation sacs have very different compositions, depending on the tissue and cell type. For example, different proteins are found in the lysosomes of liver cells than in kidney cells or in cells of cancer tumors. The protein makeup of the lysosomes can therefore provide valuable insight into the cellular roots of certain diseases.

The disposal of defective or diseased cell components is vital for our cells. The central part of the cellular waste disposal are the lysosomes – small sacs in the cytoplasm surrounded by a lipid membrane, in which dozens of different enzymes break down the introduced waste into its individual parts. The breakdown products produced by the lysosomes can then be used by the cell as raw material for further cell processes.

“The process is immensely important,” explains senior author Dominic Winter from the University Hospital Bonn. “If it doesn’t work properly, diseases such as Alzheimer’s or Parkinson’s can result.” The lysosomes and their breakdown activity are also of crucial importance for the energy metabolism of the cell, the defense against pathogens or repair mechanisms. Their structure is correspondingly complex: If you isolate lysosomes from cells, you will often find more than 5,000 different proteins.

Inventory of lysosomal proteins

However, it has so far been difficult to determine what function these proteins have in detail and how many of them are actually involved in the breakdown activity of the lysosomes. “It can also be molecules that are being broken down in them,” explains Winter. “Others may be attached to their membrane from the outside without performing any task. And there is usually a lot of unwanted by-catch when the lysosomes are isolated.”

For this reason, Winter, first author Fatema Akter from the University of Bonn, and her team have developed a method with which uninvolved molecules can be better distinguished from real lysosomal proteins. For their study, they applied these analysis methods to six different cell lines, four from humans and two from mice. The human cell cultures came from the kidneys, the cervix, the liver and the bone marrow and some had been taken from cancer tumors.

Equipment varies depending on the cell type

The analyzes revealed: Of the 5,000 proteins, a good 1,000 are more closely linked to the function of the lysosomes. A few hundred of these proteins were found in almost all lysosomes – regardless of which tissue they came from. In addition, however, there are many proteins that appear to be found only in the lysosomes of certain tissues. Other proteins, on the other hand, differ in their proportion and quantity depending on the cell type.

“In each of the six cell types that we examined, the lysosomes have a very specific protein configuration,” reports Winter. “As far as I know, we are the first working group that was able to show this.” The disposal factories of the cells are therefore specifically structured depending on the tissue and cell type and each have their own set of protein tools adapted to the needs of the cells.

More breakdown enzymes in the liver, more transporters in cancer cells

“The lysosomes of liver cells, for example, are full to the brim with degradation enzymes,” reports Winter. “That is also plausible – an important function of the liver is the breakdown of different molecules.” Because the liver plays an important role in the detoxification of the body. Cancer cells, on the other hand, have a special variant of lysosomes that can supply them with building blocks for their energy metabolism in a particularly effective manner. “In the cancer cells we examined, the lysosomes contained a large number of transporter proteins,” reports Winter.

The reason for this: tumors need a lot of energy to grow, and at the same time they often have poor blood circulation. They therefore digest the surrounding tissue with the help of the lysosomes and use the breakdown products to generate energy. So that these can then be used by the cancer cell, they have to be transported back into the cell from the lysosomes – hence the many transporter proteins.

Indications of cellular roots of Parkinson’s and Co

Overall, the results help elucidate more about the function and workings of the lysosome. But they could also help elucidate the role of lysosomes in certain diseases. Some hereditary diseases are known that are based on the malfunction of the lysosomes. In addition, in recent years there has been increasing evidence that the cellular degradation factories could also be involved in cancer and neurodegenerative diseases.

It has been known for a long time that the lysosomes in certain nerve cells are altered in Parkinson’s disease. “We can now take a kind of protein fingerprint of these lysosomes and compare them with those of healthy people,” explains Winter. “That could provide clues as to how the function of the cellular shredders is changed in those affected and why this leads to neurological problems.” In the long term, this could also help to find new starting points for drugs. (Molecular & Cellular Proteomics, 2023; doi:10.1016/j.mcpro.2023.100509 )