Cutting edge Seminar
Speaker: Hozumi Motohashi (Professor, Department of Gene Expression Regulation, Graduate School of Life Sciences, Tohoku University)
Title: Cytoprotective and Anti-Aging Function of NRF2 and its Role in Sulfur Metabolism
Date&Time: 20 Oct. (Wed.) 2021, 12:00-13:00
※This seminar can also be attended through ZOOM. Please check the URL on “HIGO Cutting-Edge Seminar” at Moodle.
https://md.kumamoto-u.ac.jp/course/view.php?id=90416
Abstract
Keap1-NRF2 system is a sulfur-based cytoprotection mechanism and makes critical contributions to prevention and alleviation of various diseases relating to oxidative stress. Recent studies of ours and others also clarified that appropriate activation of NRF2 has anti-aging effects by limiting accumulation of oxidative damages of tissues. KEAP1 utilizes multiple cysteine residues for sensing electrophiles, whereas NRF2 activates various genes regulating sulfur-involving reactions. Although NRF2 enhances mitochondrial activity, a precise mechanism has not been fully understood. Based on our recent finding that mitochondrial sulfur metabolism makes a substantial contribution to mitochondrial energy metabolism, we hypothesized that NRF2 promotes the mitochondrial activity through promoting the sulfur metabolism. Since SLC7A11 encoding a cystine transporter, xCT, is a well-known NRF2 target gene, NRF2 was likely to enhance the mitochondrial sulfur metabolism by increasing the supply of their substrate, cysteine. Indeed, cystine restriction in the culture medium and xCT inhibition by sulfasalazine both decreased the mitochondrial membrane potential (MMP), suggesting that sufficient cysteine availability is required for the maintenance of MMP. To examine contributions of the mitochondrial sulfur oxidation pathway mediated by SQOR, ETHE1 and SUOX and the mitochondrial persulfide production catalyzed by CARS2 to the MMP maintenance, we knocked down each enzyme gene and examined its impact on the MMP. The MMP was significantly decreased by knockdown of these enzymes except for SUOX. Among them, we found that SQOR, encoding sulfide-quinone oxidoreductase (SQOR), is directly activated by NRF2. Increased mitochondrial membrane potential by NRF2 activation was canceled by simultaneous suppression of SQOR. These results suggest that one of the mechanisms for NRF2-dependent mitochondrial activation is the facilitation of sulfur metabolism in mitochondria following the increased cystine uptake.
References
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4. Wati SM, Matsumaru D, Motohashi H. NRF2 pathway activation by KEAP1 inhibition attenuates the manifestation of aging phenotypes in salivary glands. Redox Biol 36:101603, 2020.
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