NRF2 and supersulfides for understanding various pathogenesis
The experimental results described above suggest that the KEAP1-NRF2 system regulates mitochondrial functions by promoting mitochondrial biosynthesis, electron transport and fatty acid oxidation, in addition to the previously known function of scavenging oxidative stress. NRF2 also enhances mitochondrial activity by promoting cystine uptake, leading to the increase in the cysteine availability for the supersulfide synthesis. This multimodal contribution of NRF2 to the mitochondrial function underscores the requirement of the KEAP1-NRF2 system for the aerobic organisms, particularly, terrestrial life exposed to higher concentrations of oxygen (Yumimoto et al., 2023).
In recent years, the NRF2-mediated regulation of mitochondrial function has attracted much attention from the perspective of disease treatment. For example, in the mouse model, NRF2 activation inhibits the progression and exacerbation of aging-related diseases, such as Alzheimer’s disease and Parkinson’s disease (Esteras et al., 2016; Uruno et al., 2020). Mitochondrial dysfunction is one of the major causes for these aging-related diseases, which are thought to result from a combination of factors, such as accumulation of oxidative stress, smoldering inflammation and impaired energy production. Therefore, therapeutic agents that ameliorate all of these phenomena are desirable for the treatment of the aging-related diseases, and NRF2 inducers are expected to be ideal because various aging-related phenotypes are more or less alleviated in the genetic model of Keap1 -knockdown mouse in which NRF2 is activated in the whole body (Wati et al., 2020; Oishi et al., 2020; Zhao et al., 2022). Importantly, it has been suggested that the supersulfides are also associated with the aging-related diseases. The supersulfides have been shown to be decreased during aging in rodents and worms (Zivanovic et al., 2019). Particularly in the brain, decreased protein supersulfidation is closely associated with the progression of the pathological changes (Petrovic et al., 2021). Supersulfides are mostly likely to serve as one of the important downstream effectors of NRF2 for its anti-aging activity as well as the antioxidant and anti-inflammatory functions. Further investigation will clarify how supersulfides contribute to the human health and longevity.