Contribution of NRF2 to sulfur metabolism and mitochondrial activity
Md Morshedul Alam,
Akihiro Kishino,
Eunkyu Sung,
Hiroki Sekine,
Takaaki Abe,
Shohei Murakami,
Takaaki Akaike,
Hozumi Motohashi
Affiliations
Md Morshedul Alam
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan; Department of Genetic Engineering and Biotechnology, Bangabandhu Sheikh Mujibur Rahman Maritime University, Mirpur 12, Dhaka, 1216, Bangladesh
Akihiro Kishino
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Eunkyu Sung
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Hiroki Sekine
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Takaaki Abe
Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
Shohei Murakami
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Takaaki Akaike
Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan; Corresponding author. Department Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
Hozumi Motohashi
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan; Corresponding author. Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
NF-E2-related factor 2 (NRF2) plays a crucial role in the maintenance of cellular homeostasis by regulating various enzymes and proteins that are involved in the redox reactions utilizing sulfur. While substantial impacts of NRF2 on mitochondrial activity have been described, the precise mechanism by which NRF2 regulates mitochondrial function is still not fully understood. Here, we demonstrated that NRF2 increased intracellular persulfides by upregulating the cystine transporter xCT encoded by Slc7a11, a well-known NRF2 target gene. Persulfides have been shown to play an important role in mitochondrial function. Supplementation with glutathione trisulfide (GSSSG), which is a form of persulfide, elevated the mitochondrial membrane potential (MMP), increased the oxygen consumption rate (OCR) and promoted ATP production. Persulfide-mediated mitochondrial activation was shown to require the mitochondrial sulfur oxidation pathway, especially sulfide quinone oxidoreductase (SQOR). Consistently, NRF2-mediated mitochondrial activation was also dependent on SQOR activity. This study clarified that the facilitation of persulfide production and sulfur metabolism in mitochondria by increasing cysteine availability is one of the mechanisms for NRF2-dependent mitochondrial activation.
