Mitochondrial function and NRF2
Mitochondria are important organelles as sites of energy metabolism in aerobic respiration. Mitochondria contain TCA cycle as a part of glucose catabolism, β-oxidation pathway as a part of fatty acid catabolism, electron transport chain (ETC), oxidative phosphorylation system and sulfur oxidation pathway as a part of cysteine catabolism. One of the important functions of mitochondria is to produce ATP via oxidative phosphorylation. TCA cycle and β-oxidation pathway provide NADH and FADH2 as substrates to the ETC that generates proton gradient across the mitochondrial inner membrane leading to the ATP production. Because mitochondrial dysfunction causes increased electron leakage from the ETC and generates ROS, the KEAP1-NRF2 system has been considered to protect cells from mitochondria-derived oxidative stress (Dinkova-Kostova & Abramov, 2015; Kasai et al., 2020; Esteras & Abranov, 2022). However, recent studies have demonstrated that the KEAP1-NRF2 system contributes not only to mitochondrial redox regulation but also to the regulation of energy metabolism.
NRF2 activation contributes to enhance mitochondrial function by regulating mitochondrial biosynthesis and energy production (Dinkova-Kostova & Abramov, 2015; Esteras & Abranov, 2022). For example, NRF2 activation in skeletal muscles by KEAP1 disruption in mice increases oxygen consumption (Uruno et al., 2016), increases myosin heavy chain (MHC) I-positive slow fibers and thereby improves endurance capacity during exercise (Onoki et al., 2021). Regarding mitochondria biogenesis, NRF2 directly promotes transcription of nuclear respiratory factor-1 (NRF-1 ), a transcription factor required for mitochondrial biogenesis (Piantadosi et al., 2008), and NRF2 inducers have been shown to activate transcription of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α ) gene, which serves as a cofactor for NRF-1 (Brose et al., 2012). As to energy production, mitochondrial membrane potential and ATP production are lower in Nrf2 -deficient mouse embryonic fibroblasts and primary cultured neural cells than wild-type cells (Holmström et al., 2013). Conversely, NRF2 activation by KEAP1 suppression increases mitochondrial membrane potential and ATP production, suggesting that NRF2 promotes energy production in mitochondria. In this regard, recent transcriptome and proteome analyses revealed that factors involved in oxidative phosphorylation and the ETC are regulated downstream of NRF2 directly or indirectly (Cho et al., 2019; Gao et al., 2020; Zhang et al., 2021; Ryan et al., 2022). NRF2 also promotes the production of NADH and FADH2, which are substrates of the ETC, and indeed, the supply of these substrates is reduced in NRF2-deficient cells (Esteras & Abramov, 2022). Consistently, the transcriptome and proteome analyses mentioned above demonstrated that NRF2 activation increases the expression of enzymes related to glucose and fatty acid metabolism and citric acid cycle enzymes involved in the production of NADH and FADH2 (Cho et al., 2019; Gao et al., 2020; Zhang et al., 2021; Ryan et al., 2022).