Amazing stuff!
"Mammalian cells actively produce elemental sulfur, using it as an antioxidant to limit cell damage. While bacteria, plants and fungi are known to produce the material, this is the first time it has been detected in mammals. ...
Now, an international team has detected S8 in cells from both mice and humans. The team, ... used a polyaromatic capsule to trap and stabilise S8 through hydrophobic interactions. This allowed them to use Raman microscopy and mass spectrometry to locate and quantify the abundance of elemental sulfur. ..."
"... Antioxidants are not obtained exclusively through the diet, as the body can also synthesize them with the help of various enzymes. An international research team ... has now demonstrated a new mechanism that contributes to the body’s own production of antioxidants. The researchers showed that mammalian cells produce and store elemental sulfur in a controlled manner in the form of cyclooctasulfur (S₈), a molecule consisting of eight sulfur atoms.
At the heart of this protective system is the enzyme eNOS, which is found in many cells. It produces nitric oxide (NO), a molecule that relaxes blood vessels and thereby regulates blood pressure. The researchers have now shown for the first time that eNOS has another function: the enzyme produces cyclooctasulfur (S₈), which serves as a storage form of elemental sulfur in cells. ...
The researchers found particularly high concentrations of these “sulfur rings” in the oxygen-dependent mitochondria, the powerhouses of the cell, as well as in lipid droplets, which serve as the cell’s fat stores. Through chemical reactions, the body can use its supply of S₈ molecules to produce specialized sulfur compounds known as hydropersulfides, which act as antioxidants. ..."
From the editor's summary and abstract:
"Editor’s summary
Elemental sulfur is an inert, water-insoluble form of sulfur that is converted into biologically assimilated forms used in energy metabolism, especially in bacteria in plants. Barayeu et al. report that cyclo-octasulfur is present in millimolar amounts in mitochondrial membranes and lipid droplets in human and mouse cells ...
Octasulfur was generated by endothelial nitric oxide synthase. This process may provide a storage source for reactive hydropolysulfides that allow antioxidant defense mechanisms in mammalian cells. Supporting such a protective role, depletion of octasulfur in cultured mouse cells increased lipid peroxidation and cell death. ...
Structured Abstract
INTRODUCTION
Elemental sulfur is a central intermediate in the global sulfur cycle and is widely produced by prokaryotes, with additional evidence for its use in plants and fungi. Whether mammals synthesize, store, or use elemental sulfur, however, has remained unknown. Because mammalian cells enzymatically generate diverse reactive sulfur species, including hydropersulfides and polysulfides, we asked whether they also produce cyclo-octasulfur (S8), the most stable allotrope of elemental sulfur, for biological function.
RATIONALE
We reasoned that if mammals use elemental sulfur as a biologically meaningful metabolite, S8 should be maintained not as an incidental chemical product but as a regulated intracellular reservoir coupled to reactive sulfur metabolism.
To test this possibility, we established complementary approaches:
mass spectrometry using a polyaromatic capsule that captures and stabilizes S8, enabling its quantitative analysis, and
Raman microscopy for the direct visualization of S8 in mammalian cells and tissues.
RESULTS
In line with established knowledge, we detected S8 in bacteria and yeast and further found it in mammalian mitochondria and lipid droplets from mouse and human cells and tissues. S8 was especially enriched in lipid droplets, corresponding by extrapolation to tens of grams or more of S8 across the human body, with particularly high levels in adipocyte-rich breast cancer tissues.
We identified lipid droplet–associated endothelial nitric oxide synthase (eNOS) as a major source of S8. Recombinant eNOS converted glutathione polysulfides [e.g., glutathione trisulfide (GSSSG)] into longer sulfur chains and ultimately S8 through an NADPH-dependent sulfur-catenation reaction, where NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate; in the presence of glutathione polysulfides and the canonical eNOS substrate L-arginine, this reaction also generated the nitric oxide (NO) carrier S-nitrosoglutathione (GSNO). Functionally, depletion of endogenous S8 increased lipid peroxidation and ferroptotic cell death,
whereas S8 delivery protected adipocytes and endothelial cells from ferroptosis. Mechanistically, S8 reacted with abundant cellular thiols, such as glutathione (GSH), to generate antioxidant hydropersulfides and polysulfides that suppress lipid peroxidation.
Local delivery of solubilized S8 into joints of mice with experimental osteoarthritis also reduced lipid peroxidation in joint tissue, suggesting a potentially protective effect.
CONCLUSION
Our findings establish that mammalian cells not only synthesize elemental sulfur as S8 but also sequester it within lipid-rich compartments at concentrations that surpass those of canonical lipophilic antioxidants such as vitamin E.
This hydrophobic sulfur reservoir may provide a dynamic replenishment of redox-active persulfides, thereby linking sulfur-chain chemistry to eNOS-dependent signaling, the restraint of lipid peroxidation, and resistance to ferroptotic cell death. These results position elemental sulfur biosynthesis as an evolutionarily conserved yet metabolically adaptable antioxidant strategy, broadening the conceptual landscape of mammalian redox biology."
Fighting cell death with sulfur (original news release)
A polyaromatic capsule was used to trap sulfur molecules produced in mammalian cells
Mammalian biosynthesis of elemental sulfur.
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