Chronic Fatigue: The Nrf2 and Mitochondrial Connection

Chronic fatigue syndrome (CFS) is a condition where symptoms last more than 6 months. One identifying feature is that the overwhelming fatigue that comes with it is not resolved with rest. CFS is now recognized as a serious health condition that is known to effect the immune and neurological systems and have other physiological impacts. In my posts, I often classify CFS as an environmental illness for the sake of simplicity. I also consider multiple chemical sensitivity (MCS) and fibromyalgia (FM) as environmental illnesses. What is common in most patients with these illnesses, is that they have higher than normal levels of oxidative stress. Oxidative stress is produced by natural cellular processes or exposure to environmental toxicants. At high levels it leads to tissue damage and disease.  Currently, the true cause of these environmental illnesses are not known. 

While the cause of CFS might not be known, several theories have been proposed. One such theory is that mitochondrial dysfunction leads to the rampant increase of oxidative stress and overall, energy depletion. (1) This in turn leads to other inflammatory processes. Of course, the opposite could be true. In general, I believe that the inhibition of the Nrf2 pathway is at the root of environmental illness. The Nrf2 is a master gene regulater that regulates the natural antioxidant system in cells and neutralizes oxidative stress. It can be inhibited by many factors including TNF-a and abnormal methylation and xenobiotics. It is upregulated by natural phenols like EGCG, sulforaphane in broccoli, resveratrol and quercetin to name a few. Recent discoveries have also lead to a number of pharmaceuticals that increase expression of Nrf2. It is only in the past few years that researchers have identified a number of ways that the Nrf2 pathway promotes cellular respiration, ATP synthesis and provides other functions in the mitochondria. 

So how exactly does Nrf2 function in the mitochondria? It seems it does it in a number of ways including reducing oxidative stress by promoting the action of complex 1, regulating the expression of ATP synthase subunit α, allows for more efficient oxidative phosphorylation, increases the levels of ATP, there is better integration of fatty acid oxidation with the TCA cycle (a process that occurs through the action for example, of glucoraphanin which is the precursor of the classical Nrf2 activator sulforaphane ), it promotes biogenesis, increases PGC-1 and maintains mitochondrial integrity. (2)

While it is not known if mitochondrial dysfunction occurs in all environmental illnesses, it makes sense that it might be a possibility. In any case, there is a reason to believe that energy depletion from oxidative stress may be a factor in causing some symptoms. 

Related:
*Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

*Sexual Dimorphism in Mitochondrial Biogenesis! 
*Impairments in Muscle Function After Cigarette Exposure and Environmental Illness 
*Green Tea Catechins May Protect Cells From Particulate Matter!

1. Chronic fatigue syndrome and mitochondrial dysfunction International Journal of Clinical and Experimental Medicine, Vol. 2, No. 1. (2009), pp. 1-16 by Norman E. Sarah Myhill

2. The emerging role of Nrf2 in mitochondrial function. Free radical biology & medicine, Vol. 88, No. Pt B. (11 November 2015), pp. 179-188 by Albena T. Dinkova-Kostova, Andrey Y. Abramov.