Introduction
Oxygen respiration enables highly efficient energy production by utilizing molecular oxygen, but at the same time, it causes oxidative damage to biomolecules, which is referred to as oxidative stress. The defense mechanism against oxidative stress is essential for the survival of aerobic organisms, and the failure of the defense mechanism causes serious damage to the organisms. The KEAP1 (Kelch-like ECH (erythroid cell-derived protein with CNC homology)-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) system has been discovered as a defense mechanism against oxidative stress and plays a central role in oxidative stress response and protection (Itoh et al., 1995; Itoh et al., 1997; Itoh et al., 1999; Yamamoto et al., 2018). In addition, the KEAP1-NRF2 system has been reported to contribute to various physiological processes such as regulation of cell differentiation and proliferation (Hochmuth et al., 2011; Mitsuishi et al., 2012; Murakami et al., 2014; Murakami et al., 2017), inflammatory responses (Suzuki et al., 2017; Kobayashi et al., 2017), and anti-aging (Wati et al., 2020; Oishi et al., 2020; Zhao et al., 2022).
Being a transcriptional activator responsible for the cellular redox regulation, NRF2 directly enhances the expression of many antioxidant proteins and enzymes that regulate biochemical reactions. NRF2 is regarded as a master regulator of redox metabolism, coordinately inducing genes encoding enzymes of glutathione system and thioredoxin system as well as NADPH production. In addition, contribution of NRF2 to the mitochondrial function has been also suggested (Dinkova-Kostova & Abramov, 2015; Holmström et al., 2016; Kasai et al., 2019). Mitochondrial are essential for aerobic organisms to be better adapt to the oxidative atmosphere in the current earth environment and also have been an attractive target for the development of therapeutic agents for various diseases, especially aging-related diseases. Recetnly, it has been suggested that sulfur metabolism, especially cysteine metabolism, plays an important role in mitochondrial energy production (Akaike et al., 2017). Interestingly, the KEAP1-NRF2 system has also been shown to regulate cellular cysteine uptake and metabolism, suggesting that it is involved in mitochondrial energy metabolism via regulation of sulfur metabolism (Alam et al., 2023). In this review article, we overview recent advances in the molecular mechanisms regulating NRF2 signaling and its contribution to metabolism and introduce important roles of sulfur metabolism in the regulation of mitochondrial functions dependent on the KEAP1-NRF2 system.