Reactive oxygen species (ROS) are produced during normal metabolism and serve many physiological functions, such as in signaling and pathogen defence. However if left unchecked they have the capacity to over-oxidise biomolecules (e.g. metabolites, proteins, lipids and DNA) causing cell dysfunction and death. Therefore ROS are buffered by antioxidant systems which maintain a balanced cellular reduction-oxidation (redox) environment. Increased levels of ROS or a failure to buffer them, increases cellular oxidation and damage, a state known as ‘oxidative stress’, which occurs in many chronic diseases including ME/CFS.
Since excessive oxidation is potentially extremely damaging, cells have evolved highly conserved adaptive responses which aim to quickly restore redox homeostasis. This is achieved via redox signaling. Many proteins are extremely sensitive to the redox environment because they contain cysteine residues. Oxidation of protein cysteine residues triggers a conformational change which alters metabolic or signaling activity. Some of these proteins are transcription factors which regulate huge genetic programmes. The most important oxidation and stress sensitive transcription factor is Nrf2, which binds antioxidant response elements (AREs) and induces the transcription of a battery of antioxidant and cytoprotective genes. Note several other important pathways also respond to oxidative stress (e.g. p53, FOXO, PPARγ and HSF1).
My table above shows some of the major shifts in cellular metabolism induced by oxidative stress and Nrf2. When all changes to metabolic pathways are viewed together, you can see how the changes in metabolism help push the cell back toward homeostasis. Evolution has placed redox-sensitive molecules in the right places!
Briefly, mitochondria are normally the major source of ROS in a cell, so oxidative suppression of mitochondrial activity and increased uncoupling (proton leak) helps lower ROS production, while mitophagy acts to remove damaged mitochondria. Suppression of cholesterol and lipid synthesis spares NADPH, while β-oxidation of lipids supports energy production. Suppression of glycolysis spares glucose, which can instead feed the PPP and carbon metabolism for NADPH regeneration. Suppression of methylation and activation of transsulfuration promote homocysteine catabolism to cysteine. Nrf2 induction of NADPH producing enzymes, cysteine uptake and antioxidant systems promotes a reducing milieu, which neutralises ROS/RNS and reduces oxidised proteins. Oxidative damage to DNA is reversed by induction of repair enzymes. Excessively damaged proteins and macromolecules are removed via increased proteasomal activity and autophagy, where they are catabolised into basic components and re-enter cellular metabolism. Induction of the non-oxidative branch of the PPP and purine synthesis supports the production of nucleotides for redox cofactors (FAD and NAD+), ATP and DNA.
These are the kinds of initial metabolic changes that oxidative stress may induce in chronic diseases. Research in this area will be important for understanding the connections between cellular redox and metabolism in health, disease and ME/CFS.