Cellular organelles known as lysosomes, which serve as cells’ factories for cell disintegration, have been discovered by researchers at Duke-NUS Medical School and associates in Singapore to transport damaged membrane lipids out of them. The results were published in the Proceedings of the National Academy of Sciences. They help us learn more about how the lysosome works in both health and illness.
According to Ms. Menglan He, co-first author of the study and an MD-PhD candidate on the Integrated Biology and Medicine PhD track at Duke-NUS, “lysosomes are tiny organelles found in cells throughout the human body, responsible for breaking down cellular waste products and salvaging reusable molecules as building blocks for cellular components.” “Rare genetic disorders that affect lysosome function result in a build-up of toxic cellular waste products that affect other organelles and result in organ and cellular pathologies, such as neurodegeneration.”
For the study, he and a multidisciplinary team of Singaporean researchers screened a panel of transporter proteins whose functions have not yet been completely understood for the study. The major facilitator superfamily (MFS), which includes the proteins that they screened, is crucial for the movement of molecules across cell membranes.
They discovered that phosphatidylcholine and phosphatidylethanolamine, two phospholipids that are essential for the structure and function of living cells, are broken down into products that are transported from lysosomes into the cytoplasm by an MFS protein known as Spns1. The two molecules are then put back into the cell through pathways that turn them back into their original lipid forms.
Dr. Alvin Kuk, a co-first author of the study and a Postdoctoral Research Fellow with the Cardiovascular & Metabolic Disorders (CVMD) Programme at Duke-NUS, continued, “Scientists know quite a lot about the molecular processes involved in breaking down and transporting some molecules out of lysosomes. However, very little is known about the two lipids, phosphatidylcholine and phosphatidylethanolamine, which make up the majority of the phospholipids in cell membranes.
The researchers discovered that Spns1 deficiency caused the pathological accumulation of the two lipids’ breakdown products inside lysosomes in both cells and preclinical models. This accumulation caused a variety of disease states, including signs of increased inflammation.
Professor David Silver, the study’s lead senior co-author and deputy director of the CVMD Programme at Duke-NUS, said, “Historically, it has been challenging to identify lysosomal lipid transporters, limiting our understanding of the role of the lysosome in lipid metabolism and disease.” This study gives us a way to look at how this new transporter works and what it means for health and illness.
Federico Torta, an assistant professor at the National University of Singapore‘s Yong Loo Lin School of Medicine and a senior study co-author, said, “This has been a fantastic collaboration.” By combining the findings of our Duke-NUS colleagues with our lipidomic data, we were able to better understand the role of Spns1. “High resolution and sensitivity mass spectrometry-based lipidomics of tissues, cells, and isolated lysosomes allowed for the detection of quantitative and qualitative changes in their lipid composition.”
