Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

When you are talking about biological pathways there is never a linear path where one protein action only leads to another. It would make understanding these pathways alot simpler but it just does not work that way. Of course, if this were so, it would be so easy for everything to just stop working if something went wrong. When there are multiple pathways that intersect, run parallel or make feedback loops on proteins that ultimately activate other proteins, it results in a kind of "checks and balance system" inside a cell. This provides a safety mechanism so processes keep working or at least "keep chugging along" even if one protein or even a few proteins that make up a pathway are damaged, are lost or their signals get misdirected. It is easy to get confused when thinking about all those protein interactions at the same time. For me.... it is easier to break the activities down and focus on the processes individually. It makes it easier to understand how these pathways work and easier to remember just what they do! (If you would like to see a graphical depiction of the tangled mess these pathways make - click here!) Today's focus is on mostly on the PGC1a pathway and its relevance to the molecular biology of environmental illnesses.

In a recent blog, I wrote about my interest in nutrition as well as, a variety of other topics I have studied that impact health and wellness. In that blog, I discussed how a number of dietary excesses or deficiencies may influence environmental disease. Specifically dietary deficiencies include vitamin D, vitamin B and folate and also may include methionine(either too little or too much). I added changes in human dietary patterns and lifestyles over the last several decades or more may have contributed to this. There is debate on whether we get too much or too little methionine from our diet. The most recent articles provide evidence that methionine actually increases mitochondrial stress and lack of DNA repair even though others recommend supplementation of methionine. Generally, our bodies use methionine to make something called s-adenosyl methionine (SAM) which is used for biosynthesis of hormones like dopamine and serotonin. (Deth, Cully) It breaks down into homocysteine which can be toxic at excess amounts but with the help of B6, B12 and folate it recycles back into methionine or glutathione. (This means we have to have substantial amounts of these nutrients too!) Methionine can also be used to make cysteine, cartinine, taurine and lecithin. Excess levels of homocysteine (homocysteinemia) has been demonstrated to have negative effects on the cardiovascular system, impair the urea cycle and may produce problematic cognitive effects. It has recently been demonstrated that PGC-1a effects homocysteine metabolism and overexpression of the antioxidant may elevate levels of homocysteine and lower PGC-1a expression is associated with lower plasma homocysteine levels. Low levels of homocysteine can alter the normal metabolism of glutathione, taurine and sulfate and therefore can be a health concern. Because homocysteine is the intermediate in the production of methionine to cysteine, it may make one more susceptible to oxidative stress and certain toxic exposures. In these cases, NAC, methionine and taurine are often recommended.

Now that we have reviewed how PGC-1a interacts with the methionine synthase pathway, let us now discuss more about this protein and its importance for maintaining overall cellular metabolism and homestasis. Homeostasis inside cells can be severely impaired without proper expression of PGC-1a because its expression influences the regulation of a number of other proteins including the PPARS, estrogen, thyroid hormone, glucocorticoids and the pregnane X receptor, just to name a few. (Finck) To demonstrate this take for example how the pregnane X receptor interacts with PGC-1a in the synthesis of CYPA26 and CYPA34. These are two enzymes necessary for the metabolism and/or detoxification of certain anesthetics, antidepressants, nicotine and other contaminants like certain molds. Additional key targets for PGC-1a include NRF1 and NRF2 which regulate mitochondrial function. The former, NRF1, is regulated by Nrf2 and taken together, Nrf2 and PGC-1a are responsible for most of the activities that promote oxidative stress resistance and cellular survival in toxic environments. PGC-1a also interacts with vitamin D and "because the expression of PGC-1α is regulated by environmental stimuli, such as diet and lower temperatures, it follows that the function of VDR could be influenced in response to these external stimuli in the tissues that exhibit an overlap in the expression of PGC-1α." (Savkur)

The PGC-1a gene responds to a number of different environmental cues including diet like fasting, caffeine, exercise and cold exposure and is preferentially expressed in tissues with high oxidative capacity. (Finck) On the other hand, it is inhibited by obesity, lack of exercise and the exposure to endotoxin. These factors lead one to consider important policy and regulatory concerns for the elderly and vulnerable populations, those with access issues to proper nutrition or individuals living with unhospitable conditions like contaminated water supplies. In general, the inhibition of PGC-1a expression has a variety of physiological effects including lower cardiac function, lower mitochondrial function, endothelial and epithelial dysfunction, poor thermoregulation, lower protection against environmental toxins, reduced energy metabolism, alterations of muscle fiber type and numerous others. One will note, all of these contribute to a variety of complications indentified in patients with environmental illnesses. As Patti describes, one complication from reduced PGC-1a expression leading to oxidative stress and altered cellular metabolism is insulin resistance and diabetes. As we noted earlier, PGC-1a interacts with NRF-1 a nuclear respiratory factor. This author demonstrates that although NRF-1 is reduced in diabetics, a number of other proteins that interact with and including PGC-1a such as PGC-1b, PPAR-gamma and NRF1 are also reduced in members of their families. From this it is assumed that decreased expression of PGC-1a is responsible for a decrease in NRF genes and the associated disturbances of insulin resistance and diabetes.

At this point, it would be worth suggesting here that metabolic disturbances may not only be the result of a reduction in expression in PGC-1a but may also be due to a reduction in the expression or regulation of NRF1 by Nrf2 at least in some cell types. One protein that has been implicated in a number of mental and physical health disorders, GSK-3b, is like an off and on switch for the Nrf2 antioxidant system that allows for cellular stress resistance. Also, other proteins may participate and PGC-1a inhibition. Tnf-a from cigarette smoke inhibites PGC-1a and may be a "key step" to vascular and myocyte dysfunction. (Tang) Both NRF1 and NRF2 are involved in the generation of the respiratory chain and it seems NRF1's role includes inducing gene expression and maintaining cytochrome C levels. An interesting article explains that several pathways exist that inhibit PGC-1a which may be different in different tissues. In addition to possible inhibition of PGC-1a in hepatocytes by Akt/PKB, there is evidence expression of PGC-1a can be dependant on reduction of a ligase called Cdc4 or through the activation of GSK-3b which also contributes to neuroinflammation. GSK-3b increases in response to oxidative stress and can regulate the TH1/Th2 balance (Ohtani) and its inhibition according to one author may lead to "stabilization of PGC-1a". Cdc4 is elevated in Parkinson's disease and as one author mentions, "it will be interesting to see if Cdc4 is responsible for the reduction of PGC-1a in the brains of PD patients." (Olson) For GSK-3b, metallothionein which can be upregulated by Nrf2 is an effective inhibitor of GSK-3b and prevents a number of diabetic-induced changes in inflammation, nitrosative stress and energy metabolism. (Wang) In cardiac cells the presense of metallothionein "abrogates mitochondrial damage, loss of mitochondrial DNA and downregulation of PGC-1a and its downstream targets. In this article the author proposes eNOS uncoupling induces the down-regulation of PGC-1a, NRF1, NRF2 and other proteins which contributes to the loss of mitochondrial biogenesis while saying further the precise mechanism for loss of mitochondrial biogenesis under eNOS uncoupling is not known. It might be important to stress here that it is now understood that Nrf2 is an important protective component against eNOS uncoupling. (Heiss) Recent evidence provides evidence of an alternative mechanism involving elevations in CO and H2O2 activates mitochondrial biogenesis through PGC-1a independantly of eNOS. In any event, PGC-1a expression is vital for normal heart function, because reductions in expression of PGC-1a results in compromised function. Other important inducers of PGC-1a include cAMP, CAMKII, AMPK and NO.

Numerous studies demonstrate and as we mentioned earlier, exercise elevates both PGC-1a gene and protein expression. As Wright explains, "with this discovery it was initially believed that exercise-induced biogenesis was mediated by increases in PGC-1a but suggests that activation of PGC-1a mediates mitochondrial biogenesis rather than the increases in protein expression." His study provides support for this because a) PGC-1a regulates binding of NRF1 and NRF2 and he demonstrates that their binding increased after exercise but before there was an increase in PGC-1a protein expression and b) a number of mitochondrial constituents were increased beforeelevations in protein levels. Other studies have demostrated that P38 activation is linked to an adaptive increase in mitochondrial biogenesis. Wright agrees and believes that generally PGC-1a production occurs in this order 1) exercise activates P38 which in turn activates PGC-1a 2) PGC-1a activates transciption factors and nuclear receptors that regulate mitochondrial expression which is part of the first phase of an adaptive response, 3) activation of the PGC-1a by the promoter and transcription factors coactivated by PGC-1a results in an increase in PGC-1a expression and 4) this mediates the second phase of an adaptive response and includes sustaining and enhancing mitochondrial biogenesis by PGC-1a. With all this in mind, one must consider that mitochondrial biogenesis and homostastic metabolism is dependant at least in part on participation of Nrf2 antioxidant system because it also regulates NRF1 and therefore, impairments of this system may contribute to conditions in metabolism where PGC-1a plays a central role.

Notes:

• Lipoic acid increases mitochondrial biogenesis and improves muscular energy through a AMPK-PGC-1a pathway which increases GLUT4 expression in aged mice. (Wang)

Original document and citations.