University of Chicago researchers discover crucial protein for cellular function
CHICAGO (CBS) -- Lysosomes – membrane-bound structures within each cell of humans and all animals – are sometimes known as the cells' "garbage disposals" or "cellular janitors."
The structures are full of enzymes that can break down all different substances – including proteins, nucleic acids, carbohydrates, and lipids – so their components can be recycled. As explained in the Annual Review of Pharmacology and Toxicology, lysosomes are also responsible for repairing damaged cellular membranes, and destroying damaged cellular components, or organelles – among other critical functions.
Lysosomes' function is driven by signals involving calcium ions (Ca2+). These ions are important messengers both within and between cells, and are involved in regulating nearly all the body's functions.
For lysosomes specifically, all their functions all involve fusion with other organelles in a cell, which is triggered by the release of those Ca2+ ions. Lysosomes also serve as storage facilities for calcium ions.
But how do those calcium ions get into the membrane-enclosed lysosomes to make them tick? That question was the subject of a new study and a groundbreaking discovery by researchers at the University of Chicago.
The study was conducted by researchers from the lab of UChicago Professor Yamuna Krishnan and published Feb. 15 in the journal Science Advances. The researchers identified a protein responsible for a key role in getting calcium ions into the lysosomes.
Lysosomes were discovered in the 1950s by Belgian scientist Christian René de Duve (1917-2013), who had been researching the enzymes involved in breaking down carbohydrates in the liver. Scientists have understood how lysosomes release their calcium as long as they have been known, UChicago explained.
"But lysosomes must also be able to 'inhale' Ca2+ after its lumen empties its Ca2+ or else it would be like a soldier who shoots once and dies - terribly wasteful for the cell," Professor Krishnan wrote. "But who is responsible for sucking Ca2+ into the lysosome, so that it can resume functioning?"
This was the question the researchers set out to answer – and such research has long been easier said than done.
"Part of the problem has been an inability to measure calcium inside the lysosome," Matthew Zajac, the first author of the paper on the study, said in a UChicago news release. "Because it's a highly acidic compartment, it's been hard to measure the calcium without that acidity interfering with measurements."
But the Krishnan lab dealt with that problem by developing a pH-correctable sensing device called the CalipHour – which can report calcium concentrations in cellular components without being hindered by acidic conditions, UChicago said.
Using these means, the team identified a protein responsible for getting calcium ions into lysosomes. This could have major implications for medicine in the future.
UChicago said the protein could serve as a target for modulating lysosomal function – and thus helping treat neurogenerative disorders such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease – all of which involve lysosomal dysfunction. Some neurogenerative diseases involve lysosomes in neurons that are not releasing their calcium ions – and thus swell up with too much calcium, researchers said in the release.
Krishnan explained on X that every channel for calcium ion transport on the lysosome is also a risk gene for a different neurodegenerative disease.
"We hope to determine that if you could find a way of blocking how lysosomes intake calcium, then you can sort of correct for that defect in export," Zajac was quoted by UChicago.
The group's drive to find the protein that transports calcium into lysosomes was spurred by a grant proposal that was rejected, UChicago said. A reviewer on the grant questioned how the researchers knew there even was any protein that brought calcium into lysosomes, the university said.
Zajac was quoted saying the mission to find the protein involved a "grueling couple of years," but Krishnan was credited for keeping her team motivated toward the goal.
While the study was in progress, Krishnan also published a series of posts on X, formerly Twitter, to document the research – and explain how lysosomes and calcium ions work in layman's terms.
Researchers now plan to study the protein further, and explore other lysosomal calcium transporters, UChicago said.
