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Sphinganine-induced lysosomal membrane permeabilization: Interplay with subcellular oxidative levels
Guodong Cheng1, Changxi Qi2, Huiling Xu1
1College of Veterinary Medicine, Shandong Agricultural University, Tai'an, Shandong, 271018, China.
Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids
|November 10, 2025
Summary
Sphinganine (SA) causes cell death primarily through lysosomal damage, not direct oxidative stress. This finding offers new therapeutic strategies for sphingolipid disorders.
Area of Science:
- Cell Biology
- Biochemistry
- Toxicology
Background:
- Sphinganine (SA) is a key sphingolipid with poorly understood cytotoxicity.
- Sphingolipids play crucial roles in cellular functions and diseases.
Purpose of the Study:
- To elucidate the precise mechanisms underlying sphinganine-induced cytotoxicity.
- To investigate the roles of reactive oxygen species (ROS) and lysosomal integrity in SA toxicity.
Main Methods:
- Cellular assays to assess cell death pathways.
- Mitochondrial and lysosomal function analysis.
- Measurement of hydrogen peroxide levels in cellular compartments.
- Inhibition studies using E64D to block cathepsin release.
Main Results:
- SA induces cell death predominantly via lysosomal membrane permeabilization (LMP) due to pH and osmotic imbalance.
- Mitochondrial ROS contribute to oxidative stress and mitochondrial fragmentation.
- Lysosomes colocalize with hydrogen peroxide microdomains, indicating redox-dependent organelle positioning.
- Inhibition of cathepsin release by E64D attenuates SA-induced apoptosis, confirming LMP's role.
Conclusions:
- SA exhibits a dual organelle toxicity mechanism targeting both mitochondria and lysosomes.
- Lysosomal membrane permeabilization is a key executor of SA-induced apoptotic signaling.
- Findings provide a therapeutic rationale for treating sphingolipid disorders, including fumonisin B1 toxicity, via lysosomal stabilization or ROS modulation.
