NRF2 Rewires Cellular Metabolism to Support the Antioxidant Response

The transcription factor (nuclear factor-erythroid 2 p45-related factor 2, NRF2) is a master regulator of the cellular response to oxidative insults. While antioxidant response enzymes are well-characterized transcriptional targets of NRF2, it is recently becoming clear that NRF2 also supports cellular detoxification through metabolic rewiring to support the antioxidant systems. In this chapter, we discuss the regulation of NRF2 and how NRF2 activation promotes the antioxidant defense of cells. Further-more, we discuss how reactive oxygen species influence cellular metabolism and how this affects antioxidant function. We also discuss how NRF2 reprograms cellular metabolism to support the antioxidant response and how this functions to funnel metabolic intermediates into antioxidant pathways. This chapter concludes by exploring how these factors may contribute to both normal physiology and disease. transports cystine into the cell which is reduced to cysteine via TXNRD, and glutamate is generated by glutaminase 1 (GLS1) and GLS2 using glutamine as a substrate. Furthermore, xenobiotics undergo oxidation, reduction, or hydrolysis by cytochrome P450 enzymes and are subsequently conjugated with glucuronic acid, catalyzed by UDP-glucuronosyltransferase (UGT), and exported out of the cells by multidrug resistance-associated proteins (MRP). Some of the xenobiotics such as quinones can undergo redox cycling which results in ROS production, which is counteracted by the NADPH-required reduction reactions catalyzed by aldo-keto reductase (AKR) and NAD(P)H: quinone oxidoreductase 1 (NQO1). The role of NRF2 in mediating the antioxidant response is through (1) regulation of NADPH-generating enzymes (G6PD, PGD, IDH1, and ME1); (2) upregulation of the enzymes required for GSH production, regeneration, and utilization, such as GLS1/GLS2 and GCLM/GCLC; (3) regulation of XCT to increase the intracellular cysteine pool in support of GSH synthesis; and (4) upregulation of UDP-glucuronosyltransferase (UGT) to promote glucuronidation pathway. α-KG dehydrogenase complex. Succinyl-CoA is then trans-formed to succinate by the succinyl-CoA synthetase. is oxidized to fumarate the succinate dehydrogenase (SDH) complex and hydrated to malate by fumarate hydratase (FH). Oxidation of malate, catalyzed by malate dehydrogenase, finally regenerates oxaloacetate, and the cycle continues.

• Publication year

  2016

• Venue

  Unknown venue

• Publication date

  2016-12-21

• Fields of study

  Biology, Medicine, Chemistry, Environmental Science

• Identifiers
  DOI 10.5772/65141
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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