Sphinganine-induced lysosomal membrane permeabilization: Interplay with subcellular oxidative levels

Abstract

Sphinganine (SA), a fundamental sphingolipid whose cytotoxicity remains incompletely characterized, has received less attention compared to other sphingoid bases. Here, we demonstrate that SA predominantly triggers cell death via lysosomal membrane permeabilization (LMP) resulting from pH dysregulation and osmotic imbalance, rather than through direct ROS-mediated mechanisms, although mitochondrial ROS contribute to oxidative stress. SA-induced mitochondrial fragmentation significantly increased hydrogen peroxide levels in both the mitochondrial matrix and intermembrane space (IMS). Strikingly, lysosomes exhibited spatial colocalization with elevated hydrogen peroxide microdomains under SA exposure, suggesting a redox-dependent mechanism governing organelle repositioning. The cysteine protease inhibitor E64D attenuated SA-induced apoptosis through suppressing cathepsin B/L release, confirming lysosomal membrane permeabilization as an executor of apoptotic signaling. These findings unveil SA's dual-targeting organelle toxicity mechanism. Our study not only elucidates key aspects of sphingolipid-mediated cytotoxicity but also provides therapeutic rationale for counteracting fumonisin B1 (FB1)-induced pathologies and related sphingolipid disorders, potentially through lysosomal stabilization or targeted ROS modulation.