Mitochondrial Stress May Cause An Immune Response, Inflammation and Depression!

"Humans and other mammals react to stressful situations through a series of well-orchestrated evolutionary adaptations. When faced with a predator looking for its next meal, or with worry of losing a job, our bodies release a cascade of stress hormones. Our heart rate spikes, breath quickens, muscles tense up and beads of sweat appear." Read more...

Brain’s Dumped DNA May Lead to Stress, Depression. New research suggests genetic material from the mitochondria can trigger an immune response throughout the body. Knvul Sheikh. Scientific American. September 13, 2018

Electroacupuncture Raises Energy Levels In Chronic Fatigue Syndrome Model!

PGC-1 is a transcription coactivator that is responsible for a number of regulatory functions of cellular metabolism. It stimulates mitochondrial biogenesis and promotes muscle fiber type that is metabolically more oxidative than glycolytic which is about 15 times more efficient. It is present in high amounts where mitochondria is present like brown fat, the heart and muscle. Increased transcription of PGC-1 induces Nrf1 and Nrf2 to increase expression of mitochondrial transcription factors and other mitochondria subunits along the transport like ATP-synthase. (1)

While the cause of chronic fatigue is not known, many experts believe that symptoms of fatigue may be due to mitochondrial dysfunction where the muscles produce less energy. One study in Great Britain demonstrated that 70% of chronic fatigue syndrome (CFS) patients   have ultra structurally abnormal mitochondria.  (2)In a more recent study published just last month, researchers analyzed the benefits of electroacupuncture (EA) ST-36 on the metabolism of CFS-model in rats. They divided the mice into 4 groups; the control group, the CFS-model mice, an EA-"Zusanli" and a non-""Zusanli group. Measurements for ATP-synthase, PGC-1, AMPK and SIRT1 were taken. After forced exercise, the levels of ATP-synthase and PGC-1 were greatly reduced while levels of SIRT1 were elevated. After an application of  electroacupuncture, "the grabbing force and the expression levels of ATP synthase mRNA, SIRT 1 and PGC-1 α proteins and mRNAs, and p-AMPK/AMPK were significantly up-regulated. The results seem to show that the grabbing force of the rats after EA was due to the increased levels of ATP-synthase,  AMPK, PGC-1 and SIRT1 to reduce mitochondrial oxidative stress and to increase energy ATP. (3)

Browse the Catalog and Website!

1. PGC-1alpha: a key regulator of energy metabolism. Advances in physiology education, Vol. 30, No. 4. (1 December 2006), pp. 145-151, doi:10.1152/advan.00052.2006 by Huiyun Liang, Walter F. Ward

2. Mitochondrial Dysfunction and Chronic Fatigue Syndrome. Kent Holtorf, M.D. Holtorf Medical Group.  https://www.holtorfmed.com/mitochondrial-dysfunction-and-chronic-fatigue-syndrome/

3. [Electroacupuncture of "Zusanli" (ST 36) Raises Muscular Force by Adjusting AMPK/PGC-1 α Signaling in Rats with Chronic Fatigue Syndrome]. Zhen ci yan jiu = Acupuncture research, Vol. 43, No. 6. (25 June 2018), pp. 335-340 by Jia-Zi Z. Dong, Yun-Tao T. Wei, Huan-Yu Y. Xu, et al.

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.

Fatigue as a Consequence of Changes In Cellular Metabolism and Disturbed Sleep!

In a recent article the author writes, "persistent fatigue may be a consequence of chronic low-grade inflammation leading to an imbalance in energy availability and expenditure, which can be mediated and maintained by changes in circadian rhythms and sleep. He goes on to say that associations between persistent fatigue in CFS and CRF with alterations in cellular metabolism, disturbed sleep, and, to a lesser extent, disruptions in circadian rhythm. For both CRF (cancer-relate fatigue) and CFS, multi-causal models are generally suggested including low-grade inflammation and disturbed sleep, and also alterations in stress physiological responses, genetic vulnerability, and sociodemographic factors, among others. " 




The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Frontiers in behavioral neuroscience, Vol. 12 (2018) by Tamara E. Lacourt, Elisabeth G. Vichaya, Gabriel S. Chiu, Robert Dantzer, Cobi J. Heijnen

Resveratrol may boost mitochondrial function for diabetics: Pre-clinical data

"Supplements of resveratrol, an antioxidant compound from red wine, may protect blood vessels from the detrimental effects of high blood sugar, says a new study."

Resveratrol may boost mitochondrial function for diabetics: Pre-clinical data

By Stephen DANIELLS, 05-May-2015. http://www.nutraingredients-usa.com/Research/Resveratrol-may-boost-mitochondrial-function-for-diabetics-Pre-clinical-data

Depression Affects Your DNA!

"Depression changes people down to their DNA, a new study suggests."

Depression leaves lasting mark on DNA. Science News. Tina Hesman Saey. April 23, 2015. https://www.sciencenews.org/article/depression-leaves-lasting-mark-dna

Sexual Dimorphism in Mitochondrial Biogenesis!

Zawada et al has demonstrated that growth hormone is a key regulator of mitochondrial biogenesis. In experiments with  growth hormone knockouts, he found that there are "significant sexual dimorphic differences in mitochondrial biogenesis markers including a decrease of PGC-1a, AMPk, SIRT1 and Nrf2 in brains of females compared to males. In kidneys, AMPk and SIRT1 were lower in females." You may recognize that I have written about all of these proteins in the past in relation to environmental illnesses. Now, I wonder if this sexual dimorphism in mitochodrial biogenesis can account for any of the gender differences that are seen in the prevalence of conditions such as CFS? (Bell) 

Gene expression of key regulators of mitochondrial biogenesis is sex dependent in mice with growth hormone receptor deletion in liver. Aging, Vol. 7, No. 3. (March 2015), pp. 195-204 by Ilona Zawada, Michal M. Masternak, Edward O. List, et al. http://www.citeulike.org/user/kimberlykramer2015/article/13579428

ME/CFS as a Mitochondrial Disease Prohealth (26 April 2006) by David S. Bell, MD. http://www.prohealth.com/library/showarticle.cfm?libid=13611

Mediterranean Diet and CoQ10 Reduce the Overexpression of Oxidatve Stress!

A Mediterranean diet supplemented with CoQ10 provided enough antioxidant potential to allow for a reduction in the overexpression and activation of Nrf2 and other antioxidant genes against oxidative stress in the elderly. Oxidative stress often occurs after intake of a high lipid or high carb diet! Q10 is necessary for mitochondrial function and the natural process of aging decreases levels of q10 that may lead to disease. (Deichman)  "The principal aspects of the Mediterranean diet include proportionally high consumption of olive oil, legumes, unrefined cereals, fruits, and vegetables, moderate to high consumption of fish, moderate consumption of dairy products (mostly as cheese and yogurt), moderate wine consumption, and low consumption of meat and meat products. ^{" (Wipedia)}    


Postprandial antioxidant gene expression is modified by Mediterranean diet supplemented with coenzyme Q(10) in elderly men and women. Age (Dordrecht, Netherlands), Vol. 35, No. 1. (February 2013), pp. 159-170 by Elena M. Yubero-Serrano, Lorena Gonzalez-Guardia, Oriol Rangel-Zuñiga, et al.

Abstract: Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. We have investigated whether the quality of dietary fat alters postprandial gene expression and protein levels involved in oxidative stress and whether the supplementation with coenzyme Q(10) (CoQ) improves this situation in an elderly population. Twenty participants were randomized to receive three isocaloric diets each for 4 weeks: Mediterranean diet supplemented with CoQ (Med + CoQ diet), Mediterranean diet (Med diet), saturated fatty acid-rich diet (SFA diet). After 12-h fast, volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. Nrf2, p22(phox) and p47(phox), superoxide dismutase 1 and 2 (SOD1 and SOD2), glutathione peroxidase 1 (GPx1), thiorredoxin reductase (TrxR) gene expression and Kelch-like ECH associating protein 1 (Keap-1) and citoplasmic and nuclear Nrf2 protein levels were determined. Med and Med + CoQ diets induced lower Nrf2, p22(phox), p47(phox), SOD1, SOD2 and TrxR gene expression and higher cytoplasmic Nrf2 and Keap-1 protein levels compared to the SFA diet. Moreover, Med + CoQ diet produced lower postprandial Nrf2 gene expression and lower nuclear Nrf2 protein levels compared to the other diets and lower GPx1 gene expression than the SFA diet. Our results support the antioxidant effect of a Med diet and that exogenous CoQ supplementation has a protective effects against free radical overgeneration through the lowering of postprandial oxidative stress modifying the postprandial antioxidant protein levels and reducing the postprandial expression of antioxidant genes in peripheral blood mononuclear cells.

Coenzyme q10 and statin-induced mitochondrial dysfunction. The Ochsner journal, Vol. 10, No. 1. (2010), pp. 16-21 by Richard Deichmann, Carl Lavie, Samuel Andrews

Abstract: Coenzyme Q10 is an important factor in mitochondrial respiration. Primary and secondary deficiencies of coenzyme Q10 result in a number of neurologic and myopathic syndromes. Hydroxyl-methylglutaryl coenzyme A reductase inhibitors or statins interfere with the production of mevalonic acid, which is a precursor in the synthesis of coenzyme Q10. The statin medications routinely result in lower coenzyme Q10 levels in the serum. Some studies have also shown reduction of coenzyme Q10 in muscle tissue. Such coenzyme Q10 deficiency may be one mechanism for statin-induced myopathies. However, coenzyme Q10 supplements have not been shown to routinely improve muscle function. Additional research in this area is warranted and discussed in this review.