Nrf2 activation leads to imbalance of carbon metabolism

I have long suspected that during chronic Nrf2 activation, the cells are losing glutamate, and this not only impairs the Krebs cycle but also other pathways that depend on glutamate inside the cell. These pathways include the polyglutamylation of folate, which can lead to functional folate deficiency, and the synthesis of glutathione, despite the fact that the whole purpose of Nrf2 activation is to restore the level of glutathione, etc.

Here is a study (R1) that confirms some of my suspicions regarding the possible results of glutamate depletion.

Here, we show that activation of NRF2, in either mouse or human cancer cells, leads to increased dependency on exogenous glutamine through increased consumption of glutamate for glutathione synthesis and glutamate secretion by xc- antiporter system. Together, this limits glutamate availability for the tricarboxylic acid cycle and other biosynthetic reactions creating a metabolic bottleneck. … Here we demonstrate that KEAP1 loss of function (LOF) mutations drive increased dependency on glutamine in both mouse and human KRAS-driven LUAD cell lines. We show that KEAP1 mutant cells have decreased intracellular glutamate pools through increased glutamate consumption for GSH synthesis and by exporting glutamate through the antiporter xCT in exchange for cystine.

The low intracellular pools of glutamate lead to increased sensitivity to glutamine deprivation and glutaminase inhibition in an xCT dependent fashion.

Using a small molecule activator of NRF2, we provide evidence that acute NRF2 activation is sufficient to rewire cellular metabolism, similar to that of KEAP1 mutant cells, and leads to glutamine dependency due to a basal deficiency in anaplerosis. (R1)

In layman’s terms:

When the cells have activated the stress-response chronically, it leads to many perturbations that depend on glutamate because glutamate is lost from the cells by design.

This study shows that Nrf2 activation increases dependency on exogenous glutamine.

In my model of TS: it’s the long term activation of Nrf2 + impaired autophagy that leads to reduction of GABA-A receptors and excessive glutamatergic stimulation due to spillover of exported glutamate and overloaded astrocytes from all the glutamate that they have to pick up and convert.

The paper (R2) shows that Nrf2 activation redirects glucose and glutamine and that Nrf2 activation is required for the efficient purine synthesis from glucose:

Importantly, 100% of IMP detected in the tracer study was [13C5] IMP, suggesting that the ribose ring (C5) of IMP is all derived from glucose in A549 cells. Thus, the decrease in IMP in the NRF2-knockdown cells indicates that NRF2 is required for the efficient purine nucleotide synthesis from glucose. We did not detect a significant contribution of NRF2 to the pyrimidine nucleotide synthesis. (R2)