High lumenal chloride in the lysosome is critical for lysosome function
| Autor: | Yamuna Krishnan, Kasturi Chakraborty, Ka-Ho Leung |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lysosomal storage disorders Chloride Mice 0302 clinical medicine DNA nanotechnology Biology (General) Caenorhabditis elegans chemistry.chemical_classification 0303 health sciences biology Chemistry General Neuroscience chloride biology General Medicine live imaging Enzymes Cell biology medicine.anatomical_structure Biochemistry C. elegans lysosome Medicine Research Article medicine.drug QH301-705.5 Science chemistry.chemical_element Calcium General Biochemistry Genetics and Molecular Biology Cell Line lysosomal storage disorders 03 medical and health sciences Chlorides Live cell imaging Lysosome Organelle medicine Animals Humans 030304 developmental biology cell culture 030102 biochemistry & molecular biology General Immunology and Microbiology Staining and Labeling Cell Biology biology.organism_classification 030104 developmental biology Enzyme Cell culture Lysosomes 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | eLife, Vol 6 (2017) eLife |
| Popis: | Lysosomes are organelles responsible for the breakdown and recycling of cellular machinery. Dysfunctional lysosomes give rise to lysosomal storage disorders as well as common neurodegenerative diseases. Here, we use a DNA-based, fluorescent chloride reporter to measure lysosomal chloride in Caenorhabditis elegans as well as murine and human cell culture models of lysosomal diseases. We find that the lysosome is highly enriched in chloride, and that chloride reduction correlates directly with a loss in the degradative function of the lysosome. In nematodes and mammalian cell culture models of diverse lysosomal disorders, where previously only lysosomal pH dysregulation has been described, massive reduction of lumenal chloride is observed that is ~103 fold greater than the accompanying pH change. Reducing chloride within the lysosome impacts Ca2+ release from the lysosome and impedes the activity of specific lysosomal enzymes indicating a broader role for chloride in lysosomal function. DOI: http://dx.doi.org/10.7554/eLife.28862.001 eLife digest In cells, worn out proteins and other unnecessary materials are sent to small compartments called lysosomes to be broken down and recycled. Lysosomes contain many different proteins including some that break down waste material into recyclable fragments and others that transport the fragments out of the lysosome. If any of these proteins do not work, waste products build up and cause disease. There are around 70 such lysosomal storage diseases, each arising from a different lysosomal protein not working correctly. A recently developed “nanodevice” called Clensor can measure the levels of chloride ions inside cells. Clensor is constructed from DNA, and its fluorescence changes when it detects chloride ions. Although chloride ions have many biological roles, chloride ion levels had not been measured inside a living organism. Now, Chakraborty et al. – including some of the researchers who developed Clensor – have used this nanodevice to examine chloride ion levels in the lysosomes of the roundworm Caenorhabditis elegans. This revealed that the lysosomes contain high levels of chloride ions. Furthermore, reducing the amount of chloride in the lysosomes made them worse at breaking down waste. Do lysosomes affected by lysosome storage diseases also contain low levels of chloride ions? To find out, Chakraborty et al. used Clensor to study C. elegans worms and mouse and human cells whose lysosomes accumulate waste products. In all these cases, the levels of chloride in the diseased lysosomes were much lower than normal. This had a number of effects on how the lysosomes worked, such as reducing the activity of key lysosomal proteins. Chakraborty et al. also found that Clensor can be used to distinguish between different lysosomal storage diseases. This means that in the future, Clensor (or similar methods that directly measure chloride ion levels in lysosomes) may be useful not just for research purposes. They may also be valuable for diagnosing lysosomal storage diseases early in infancy that, if left undiagnosed, are fatal. DOI: http://dx.doi.org/10.7554/eLife.28862.002 |
| Databáze: | OpenAIRE |
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