A recent study from the National University of Singapore’s Yong Loo Lin School of Medicine (NUS Medicine) has uncovered a critical mechanism by which cells regulate lipid metabolism, preventing toxic accumulation and maintaining cellular health.
Published in Proceedings of the National Academy of Sciences (PNAS), the study, led by Associate Professor Nguyen Nam Long, identifies Spinster homolog 1 (Spns1) as a key protein in the transport of lysophospholipids within lysosomes—cellular compartments responsible for breaking down and recycling biomolecules. Spns1 ensures proper lipid processing, preventing the accumulation of harmful waste products that could lead to cellular dysfunction.
Lysosomes receive lipids through three primary pathways: endocytosis, in which cells absorb external molecules; phagocytosis, where immune cells engulf large particles for degradation; and autophagy, a self-cleaning process targeting damaged cellular components. Lipids recycled in lysosomes contribute to membrane repair, energy production, and cell signaling, with molecules like sphingosine-1-phosphate (S1P) playing vital roles in cellular communication.
Dysfunction in Spns1 impairs lipid transport, contributing to lysosomal storage diseases (LSDs)—a group of over 50 rare genetic disorders, including Gaucher, Tay-Sachs, Niemann-Pick, and Pompe diseases. Defects in lysosomal processing are also implicated in neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases.
In collaboration with the University of Texas Southwestern Medical Center (UTSW), researchers utilized cryo-electron microscopy (cryo-EM) to visualize Spns1’s interaction with lysophosphatidylcholine (LPC), providing insight into its molecular function. As co-author Ms. Ha Thi Thuy Hoa explains, “While this study captured Spns1 in a state where it opens to the lysosome to take up lipids, we are now working to understand the opposite state where it opens from the lysosome to the rest of the cell.”
The study’s findings suggest that targeting Spns1 could lead to new treatments for LSDs and related disorders. Researchers are now investigating small molecules that could modulate Spns1 function, paving the way for potential drug development aimed at improving lysosomal lipid metabolism.
