Metabolism regulated by NRF2
As a key regulator of redox metabolism, NRF2 directly regulates many
enzymes and antioxidant proteins involved in the redox regulation.
Enzymes and transporters supporting glutathione synthesis and
utilization are widely regulated by NRF2, which includes catalytic and
regulatory subunits of gamma-glutamylcysteine ligase (GCLC and GCLM),
glutathione reductase (GSR), glutathione peroxidases (e.g. ,
GPX2), glutathione-S-transferase (e.g. , GSTM1 and GSTP1), and a
cystine transporter (xCT) (Figure 4) (Malhotra et al., 2010; Chorley et
al., 2012). Thioredoxin system is also under the regulation of NRF2. In
NRF2-activated cancer cells possessing hyperactivation of NRF2 and
consequently exhibiting NRF2 addiction, which is often caused by somatic
mutations of KEAP1 or NFE2L2 gene, glutathione synthesis
is greatly enhanced and thereby, cysteine, glutamate and glycine are
highly consumed and required for glutathione. In the NRF2-activated
cancer cells, the demand for cysteine is fulfilled by increased
expression of xCT (Sasaki et al., 2002), and the requirement of glycine
is covered by increased de novo synthesis from serine (DeNicola
et al., 2015) and increased dependency on the uptake of extracellular
serine and glycine (LeBoeuf et al., 2020). In contrast, glutamate is
decreased and short due to glutamate export by xCT and glutamate
consumption for the glutathione synthesis, which results in the
metabolic vulnerability of NRF2-activated cancer cells (Romero et al.,
2017; Sayin et al., 2017).
Another metabolic activity regulated by NRF2 is NADPH synthesis (Figure
4). Pentose phosphate pathway contains two enzymes for the NADPH
synthesis, glucose-6-phosphate dehydrogenase (G6PD) and phosphogluconate
dehydrogenase (PGD), both of which are target genes of NRF2 (Mutsuishi
et al., 2012; Ding et al., 2021). Other NADPH synthesis steps are
regulated by isocitrate dehydrogenase 1 (IDH1) and malic enzyme 1 (ME1),
which are also regulated by NRF2 (Mutsuishi et al., 2012). Folate
metabolism-coupled NADPH production mediated by
methylenetetrahydrofolate dehydrogenase, cyclohydrolase and
formyltetrahydrofolate synthetase 1 (MTHFD1) and MTHFD2 appears to be
partly and indirectly regulated by NRF2, especially in NRF2-activated
cancer cells where NRF2 cooperates with ATF4 (Mutsuishi et al., 2012;
Fan et al., 2014).
As mentioned above, NRF2 enhances NADPH production by re-wiring
metabolism pathway, and offer strong reducing condition. The
NRF2-mediated reducing condition is beneficial for maintaining the high
efficiency of translation because many ribosomal subunits are rather
susceptible to oxidation of cysteine residues and subsequent decline of
their functionality (Chio et al., 2016). On the other hand, continuous
stabilization of NRF2 is considered to cause excessive cellular reducing
force, that is, reductive stress. Inheritable missense mutations in
small molecular weight heat-shock proteins promotes hypertrophic
cardiomyopathy by forming protein aggregate containing KEAP1, which
causes persistent activation of NRF2 (Rajasekaran et al., 2007;
Rajasekaran et al., 2011). Under this condition, NRF2-induced reductive
stress is regarded to further promotes protein aggregation, which
exacerbates cardiomyopathy, as NRF2 suppression mitigates protein
aggregation and improves the cardiac function (Kannan et al., 2013).
Comprehensive analysis of various lung cancer cell lines also showed
that NRF2 activation increases NADH vs. NAD+, leading
to reductive stress (Weiss-Sadan et al., 2023). Consistent with these
studies, NRF2-activated cancers exhibit dependency on SLC33A1, which is
related to unfolded protein response and autophagy, possibly to avoid
protein aggregation under reductive cellular environment caused by NRF2
(Romero et al., 2020).