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.