Phytosphingosine-induced cell apoptosis via a mitochondrially mediated pathway.

Cyanobacterial blooms, usually dominated by Microcystis aeruginosa, pose a serious threat to global freshwater ecosystems owing to their production and release of various harmful secondary metabolites. Detection of the chemicals in M. aeruginosa exudates using metabolomics technology revealed that phytosphingosine (PHS) was one of the most abundant compounds. However, its specific toxicological mechanism remained unclear. CNE-2 cells were selected to illustrate the cytotoxic mechanism of PHS, and it was determined to cause excessive production of reactive oxygen species and subsequently damage the mitochondrial structure. Mitochondrial membrane rupture led to matrix mitochondrial membrane potential disintegration, which induced Ca overload and interrupted ATP synthesis. Furthermore, rupture of the mitochondrial membrane induced the opening of the permeability transition pore, which caused the release of proapoptotic factors into the cytoplasm and the expression of apoptosis-related proteins Bax, Bcl-2, cytochrome-c and cleaved caspase-3 in CNE-2 cells. These events, in turn, activated the mitochondrially mediated intrinsic apoptotic pathway. A mitochondrial repair mechanism, namely, PINK1/Parkin-mediated mitophagy, was then blocked, which further promoted apoptosis. Our findings suggest that more attention should be paid to the ecotoxicity of PHS, which is already listed as a contaminant of emerging concern.