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.