Fatty acid metabolism and NRF2-mediated mitochondrial
activation
In mammals, fatty acids are stored in adipocytes as triglycerides,
broken down into fatty acids and glycerol as needed, and released into
the blood as free fatty acids. Fatty acids taken into the cells from the
blood undergo β-oxidation in the mitochondria and are finally converted
to acetyl CoA, which enters the TCA cycle. In the process of
β-oxidation, fatty acids produce more FADH2 than NADH
compared with glucose, implying that energy production using fatty acids
is more dependent on Complex II of the ETC than that using glucose.
As mentioned above, disruption of Keap1 gene in mouse skeletal
muscles increases MHC I-positive slow fibers and improves exercise
endurance capacity (Onoki et al., 2021). Intriguingly, the NRF2
activation in the skeletal muscle promotes the fatty acid mobilization
and elevates succinate dehydrogenase (SDH) activity, implicating that
preferred utilization of fatty acids as energy source enhances the
NRF2-mediated endurance capacity. Consistent with the results, it was
reported that FADH2 production is reduced in the hearts
of NRF2-deficient mice and that fatty acid-stimulated oxygen consumption
is increased in the mitochondria of KEAP1-knockdown mice (Ludtmann ert
al., 2014), suggesting that NRF2 activation enhances β-oxidation.
Carnitine palmitoyl-tansferase 1 (CPT1) and CPT2 are required for the
uptake of fatty acids into the mitochondria and are rate-limiting
enzymes for fatty acid oxidation and both enzymes were also shown to be
decreased in cultured cells and livers from NRF2-deficient mice (Pang et
al., 2014; Meakin et al., 2014). The transcriptome and proteome analyses
suggest that NRF2 activation increases the expression of CPT1 and CPT2,
and in particular, CPT2 was reported to have an ARE sequence to which
NRF2 can bind, which implying that CPT2 is a direct NRF2 target gene
(Cho et al., 2019; Gao et al., 2020; Ryan et al., 2022). Furthermore, it
has been reported that NRF2 also directly promotes gene expression of
CD36, which is present in cellular and mitochondrial membranes and
involved in fatty acid transport (Maruyama et al., 2008). These
observations suggest NRF2 activation is involved in mitochondrial
membrane potential formation by promoting fatty acid uptake and fatty
acid oxidation.