Uladzimir Barayeu, Seiryo Ogata, Tsuyoshi Takata, Minkyung Jung, Tetsuro Matsunaga, Masanobu Morita, Tomoaki Ida, Mike Lange, Yuka Unno, Saber Boushehri, Paulius Greicius, Akira Nishimura, Lorenzo Catti, Yuexuan Pan, Tianli Zhang, Takayuki Shimizu, Ryo Ushioda, Takakazu Nakabayashi, Seji Asamitsu, Kazuki Fusegawa, Takashi Suzuki, Takanori Ishida, Naoko Tanda, Yasuo Watanabe, Yukihiro Tsuchiya, Ryo Yamaguchi, Shintaro Noguchi, Eikan Mishima, Fumiko Yano, Mieko Arisawa, Dennis J Stuehr, Ning Xia, Huige Li, Bernd Moosmann, Frauke Gräter, Camilo Aponte-Santamaría, James A Olzmann, Marcus Conrad, Albert van der Vliet, Tobias P Dick, Hozumi Motohashi, Michito Yoshizawa, Takaaki Akaike
Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo-octasulfur (S8). We found that S8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet-associated nitric oxide synthase as a source of S8 biosynthesis and found that S8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.