pH와 Macrophage의 영향

Cellular waste disposal, where autophagy and lysosomes interact, performs elementary functions, such as degrading damaged protein molecules, which impair cellular function, and reintroducing the resulting building blocks such as amino acids into the metabolic system.

Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin have now discovered a previously unknown mechanism: osmotic stress, i.e. a change in water and ionic balance, triggers a response within hours, resulting in the increased formation and activity of autophagosomes and lysosomes.

Our cells are occasionally in need of a "spring clean" so that incorrectly folded protein molecules or damaged cell organelles can be removed, preventing the aggregation of protein molecules. The mechanisms responsible for this removal are so-called "autophagy" and the closely related lysosomal system, the discovery of which earned the Nobel Prize for Medicine in 2016.

Quite a number of studies suggest that autophagy and lysosomes play a central role in aging and in neurodegenerative diseases. It is also generally agreed that fasting or food deprivation can kickstart this cellular degradation and recycling process. Other than that, little is known about how cells and organs control the quality of their protein molecules, and which environmental influences give the decisive signal to start cleaning up.

It is osmotic stress, i.e. the state in which cells lose water, that starts the system of autophagy and of lysosomal degradation.

in the event of dehydration, the ion transporter NHE7 translocates from the cell's interior, where it is normally positioned, to the cell's limiting plasma membrane that shields the cell from the outside. This leads to an influx of sodium ions into the cell, indirectly increasing the level of calcium—a key messenger—in the cytosol. The elevated level of calcium in turn activates a transcription factor called TFEB, which finally switches on autophagy and lysosomal genes. In other words, the system is initiated by the ion transporter NHE7, triggered by osmotic stress.

Counter experiments revealed the importance of this pathway for human health: when the researchers removed a component of the signaling pathway, such as the transporter NHE7 or the transcription factor TFEB, aggregated protein molecules accumulated in astrocytes under osmotic stress conditions; they could not be broken down. In the study, this phenomenon was demonstrated for components such as synuclein—a protein that plays a role in Parkinson's disease.

"In addition, NHE7 is a so-called Alzheimer's risk gene. We now have new insights into why this gene could play such a critical role."

it is not yet clear how osmotic stress affects the translocation of NHE7 to the cell surface. 

 

 

reference

Tania López-Hernández et al, Endocytic regulation of cellular ion homeostasis controls lysosome biogenesis, Nature Cell Biology (2020). DOI: 10.1038/s41556-020-0535-7