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).