Abstract
Cyclic octasulfur ( cyclo-octasulfur, S 8) is a product of sulfur respiration in bacteria. According to the endosymbiotic theory, mitochondria have evolved from sulfur bacteria, and thus it may exist in mitochondria. Using a new mass spectrometry method, we found S 8 in mammalian mitochondria at levels similar to bacteria, as concentrated in lipid droplets of mouse and human adipocytes, while bacteria store S 8 in sulfur granules. We identified that endothelial nitric oxide synthase (eNOS) and other NOS enzymes effectively produce S 8 when provided appropriate donors like glutathione trisulfide (GSSSG) together with NADPH. eNOS, activated by Ca 2+ ionophore A23187 and vascular endothelial growth factor (VEGF), exhibited a significant association and localization on the surface of lipid droplets. This led to the high yield accumulation of S 8 in lipid droplets of endothelial cells. Our results suggest that S 8 acts as a reservoir for reactive hydropersulfides, protecting cells from ferroptosis by countering lipid peroxidation. Persulfides serve as antioxidants and thus protect cells from lipid peroxidation-driven cell death - ferroptosis. Indeed, depletion of S 8 from adipocytes and endothelial cells caused lipid oxidation and ferroptosis. In contrast, supplementation with solubilized S 8 prevented ferroptosis. Our findings suggest that a previously unrecognized mammalian S 8 pool protects cells against oxidative damage and may also help even cancer cells to survive. In summary, S 8 exhibits an evolutionary conservation as a source of antioxidants and a potent regulator of lipid peroxidation. Consequently, it emerges as a crucial cytoprotective molecule, biosynthesized endogenously
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