― 267 ―Accumulating evidence has suggested that cysteine persulfide and related persulfides are found in abundant quantities in both prokaryotic and eukaryotic cells and play important roles in antioxidant and anti-inflammatory responses7-11). Among the enzymes that have been reported to possess persulfide-synthesizing activity, including cystathionine β-synthetase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST) and CARS3,9,12,13), CARS2, a mitochondrial isoform of CARS, is regarded as the major contributor to the production of persulfide-containing metabolites judging from the results of loss-of-function experiments3). This study reproduced the result showing the necessity of CARS2 for persulfide generation and mitochondrial function and demonstrated important roles of the sulfur oxidation pathway catalyzed by SQOR and ETHE1 in mitochondrial activity. Based on these results, we identified xCT-dependent cystine uptake as one of the major activities of NRF2 in promoting mitochondrial function. Considering that cystine is also a substrate of CBS and CSE for direct generation of cysteine persulfide9,14), cystine availability is most likely to be an important determinant of intracellular persulfide levels. NRF2-mediated mitochondrial activation depends on persulfide production and the sulfur oxidation pathway, verifying the significance of sulfur metabolism for mitochondrial function. Because persulfide has been reported to decrease during aging15), NRF2 activation may exert anti-aging effects via increasing cellular persulfide levels and mitochondrial robustness.We thank the Biomedical Research Core of the Institute of Development, Aging and Cancer for their technical support. This work was supported by Chugai Foundation for Innovative Drug Discovery Science (C-FINDs).Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev. 98, 1169–1203 (2018).2. Dinkova-Kostova, A.T., and Abramov, A.Y: The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 88, (Pt B), 179–188 (2015).3. Akaike T, Ida T, Wei FY, Nishida M, Kumagai Y, Alam MM, Ihara H, Sawa T, Matsunaga T, Kasamatsu S, Nishimura A, Morita M, Tomizawa K, Nishimura A, Watanabe S, Inaba K, Shima H, Tanuma N, Jung M, Fujii S, Watanabe Y, Ohmuraya M, Nagy P, Feelisch M, Fukuto JM, Motohashi H: Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics. Nat Commun. 8, 1177 (2017).4. Sasaki, H., Sato, H., Kuriyama-Matsumura, K., Sato, K., Maebara, K., Wang, H., Tamba, M., Itoh, K., Yamamoto, M., and Bannai, S: Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem, 277, 44765–44771 (2002).5. Shieh, M., Ni, X., Xu, S., Lindahl, S.P., Yang, M., Matsunaga, T., Flaumenhaft, R., Akaike, T., Xian, M: Shining a light on SSP4: A comprehensive analysis and biological applications for the detection of sulfane sulfurs. Redox Biol. 56, 102433 (2022).6. Vitvitsky, V., Kumar, R., Libiad, M., Maebius, A., Landry, A.P., Banerjee, R: The mitochondrial NADH pool is involved in hydrogen sulfide signaling and stimulation of aerobic glycolysis. J Biol Chem. 296, 100736. (2021).PerspectivesAcknowledgmentsReferences1. Yamamoto, M., Kensler, T.W., and Motohashi, H: The KEAP1-NRF2 System: a Thiol-Based Sensor-
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