The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1 (NRF-1).

WOW! I think studies have demonstrated that NRF-1 is important in its regulation with PGC-1a for mitochondrial biogenesis and regulated by Nrf2. This further supports the importance of Nrf2 in environmental disease especially those that have been associated with folate deficiency! We noted another study that broccoli has a role in regulating folate which supports the need for proper Nrf2 function.


CiteULike: The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1 (NRF-1).: "identify NRF-1 as a major inducible transcriptional regulator of PCFT gene expression. The implications of this linkage between folate transport and metabolism with mitochondria biogenesis and respiration are discussed"

Insulin signaling meets mitochondria in metabolism.

"insulin signaling underpins mitochondrial electron transport chain integrity and activity by suppressing FOXO1/HMOX1 and maintaining the NAD(+)/NADH ratio, the mediator of the SIRT1/PGC1alpha pathway for mitochondrial biogenesis and function"

CiteULike: Insulin signaling meets mitochondria in metabolism.:

PGC-1a and Sirtuin 1 (SIRT1) Reside in Mitochondria: POSSIBLE DIRECT FUNCTION IN MITOCHONDRIAL BIOGENESIS

Peroxisome Proliferator-activated Receptor {gamma} Co-activator 1{alpha} (PGC-1{alpha}) and Sirtuin 1 (SIRT1) Reside in Mitochondria: POSSIBLE DIRECT FUNCTION IN MITOCHONDRIAL BIOGENESIS [Bioenergetics]

HO-1, Nrf2 in Induction of NRF-1 and Mitochondrial Biogenesis!

"endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3β, which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter. The ensuing accumulation of nuclear NRF-1 protein leads to gene activation for mitochondrial biogenesis,"

Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1 -- Piantadosi et al. 103 (11): 1232 -- Circulation Research:

Role of CO in cardiac mitochondrial biogenesis

"Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1 (NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1, and of mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA (mtDNA). This is independent of nitric oxide synthase (NOS), as demonstrated by the identical responses in wild-type and endothelial NOS (eNOS)-deficient mice, and by the inhibition of inducible NOS (iNOS)."

A new activating role for CO in cardiac mitochondrial biogenesis -- Suliman et al. 120 (2): 299 -- Journal of Cell Science:

Nrf2 Regulation of Lipids and Glucose: Modulation of PGC-1a Through Protein

Over the past several months, I have proposed that certain environmental illnesses such as chemical sensitivity may be due to alterations in metabolic homeostasis from inflammatory processes and may include dysfunction of the antioxidant system Nrf2 and levels of PGC-1a, possibly through alterations in methylation or some other condition. Several recent studies provides a clearer picture of how this may occur in different tissues. PGC-1a is an important protein that participates in a number of processes including glucose and lipid regulation. (Kelly) In other blogs, we have explained how altered levels are apparent in the tissues of diabetes and for this reason, changes occur in metabolic function. As for Nrf2, it mitigates the effect of inflammatory cytokines as well as, upregulates proteins used in downstream processes of PGC-1a.

For several years now, it has been known that PGC-1a plays an important role in mitochondrial biogenesis and regulates cellular energy metabolism in the liver and muscle and is activated by SIRT1. SIRT1 is another protein we have discussed at length and is activated by the compound resveratrol in red wine and grape skins. Last year, one study showed that in neurons overexpression of SIRT1 or suppression of a GCN5 aminotransferase activated PGC-1a and increased mitochondrial density. Because, several experts have postulated that environmental illnesses may be due to mitochondrial dysfunction from exposures and endogenous processes, increasing mitochondrial density may reduce cellular impairment and increase neuronal survival and provide a therapeutic target.

It seems that GCN5 has the capacity to interact with the PGC family in general. Kelly et al recently found that GCN5 interacts with PGC-1b to repress its transcription activites associated with the estrogen receptor and NRF-1. As a result, the induction of GLUT4 and MCAD were reduced in skeletal muscle which translates to a blunted response of insulin-mediated glucose transport and increases the likelihood of the role of both PGC-1a and PGC-1b in metabolic disease.

As far as Nrf2 goes, in the liver the enzyme ATP citrate lyase (ACL)"relates energy balance" to GCN5 through the control of acetyl-CoA. In a new study by Kitteringham, the findings provide evidence that Nrf2 negatively regulates ATP citrate and therefore may provide a more influential role in glucose and lipid regulation than previously thought. (Kitteringham)

Notes:
***NO derived from constitutive nNOS plays a crucial role in the activity pattern of mitochondrial enzymes. In particular, the NO-mediated suppression of citrate synthase activity may be attributed to a regulatory function of NO in fatty acid synthesis. Inhibition of mitochondrial respiration by NO appears to be at least partially compensated for by a respective increase in the activity of respiratory chain complexes. (Schild) One could suggest the actions of Nrf2 may assist in the regulation of this function.



Kitteringham, N. R., Abdullah, A., Walsh, J., Randle, L., Jenkins, R. E., Sison, R., Goldring, C. E., Powell, H., Sanderson, C., Williams, S., Higgins, L., Yamamoto, M., Hayes, J., and Park, B. K. (2010). Proteomic analysis of nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary nrf2-dependent pathways in the liver. Journal of proteomics, 73(8):1612-1631.
http://www.citeulike.org/user/HEIRS/article/7329576

Jeninga, E. H., Schoonjans, K., and Auwerx, J. (2010). Reversible acetylation of pgc-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene, aop(current).
http://www.citeulike.org/user/HEIRS/article/7282171

Wareski, P., Vaarmann, A., Choubey, V., Safiulina, D., Liiv, J., Kuum, M., and Kaasik, A. (2009). Pgc-1alpha and pgc-1beta regulate mitochondrial density in neurons. The Journal of biological chemistry, 284(32):21379-21385.
http://www.citeulike.org/user/HEIRS/article/4965303?show_msg=already_posted

Kelly, T. J., Lerin, C., Haas, W., Gygi, S. P., and Puigserver, P. (2009). Gcn5-mediated transcriptional control of the metabolic coactivator pgc-1beta through lysine acetylation. The Journal of biological chemistry, 284(30):19945-19952.
http://www.citeulike.org/user/HEIRS/article/5199678?show_msg=already_posted

Schild, L., Jaroscakova, I., Lendeckel, U., Wolf, G., and Keilhoff, G. (2006). Neuronal nitric oxide synthase controls enzyme activity pattern of mitochondria and lipid metabolism. FASEB J., 20(1):145-147.
http://www.citeulike.org/user/HEIRS/article/7329782

Neuroprotection through Stimulation of Mitochondrial Antioxidant Protein Expression.

Nrf2 system and its protection against mitochondrial bioenergetic dysfunction may therefore constitute a powerful mechanism for both pre-conditioning against neurodegeneration and for post-conditioning against neural cell death associated with acute neurologic injury.

CiteULike: Neuroprotection through Stimulation of Mitochondrial Antioxidant Protein Expression.: "Greco, T. and Fiskum, G. (2010). Neuroprotection through stimulation of mitochondrial antioxidant protein expression. Journal of Alzheimer's disease : JAD."

NO-cGMP and Mitochondrial Biogenesis -- Mediator of PGC-1a

As we have noted, hyperammonia may impair the NO-cGMP pathway. Nisoli explains, "nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance."

Nisoli, E., Clementi, E., Paolucci, C., Cozzi, V., Tonello, C., Sciorati, C., Bracale, R., Valerio, A., Francolini, M., Moncada, S., and Carruba, M. O. (2003). Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science (New York, N.Y.), 299(5608):896-899. http://www.citeulike.org/user/HEIRS/article/7030900





HEIRS Environmental Illness Research Blog: Dysfunction of Methylation and Nrf2 in Environmental Illness - A Better Explanation than NO/ONOO- ?

Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness

As we have noted the Nrf2 regulates a number of genes including those that are important for mitochondrial biogenesis and other homeostatic functions and the expression of it can be effected by age, injury, oxidative stress, nutrition and other behavioral factors. As Dhar shows, the NRF-1 transcription factor upregulated by Nrf2 and important for PGC-1a activation and mitochondrial biogenesis has been shown to co-regulate a number of different genes including that for NR1, NR2b and Cox1. The Nr2b is a subunit of the NMDA which has been implicated in nociception of MCS upon upregulation (Pall) as well as, has been implicated in having involvement in other environmental illnesses including fibromyalgia. Its involvement also provides important implications for conditions of learning and cognitive difficulties that usually are co-morbid with these conditions. There does seem to be some debate on whether NMDA is upregulated or down-regulated and it may be that specific situations influence this. Yonden previously demonstrated that the downregulation of the NR2b receptor occurs with addition of experimental ammonia and concluded that downregulation of the NMDA contributes to severity of hepatic encephalopathy. This also supports our opinion that Nrf2 may influence environmental conditions including MCS and others because it is important for regulation of NRF1. It also provides supporting evidence that other health conditions where mitochondrial dysfunction is a factor, may also be influenced by the expression of Nrf2 because NRF1's role in mitochondrial biogenesis.

HEIRS Tags: NR2B, NRF1, hyperammonia,
For Further Reading: Nrf2, Ornithine Transferase, Autism and Maternal Age -- A Possible Link?

CiteULike: Coupling of Energy Metabolism and Synaptic Transmission at the Transcriptional Level: Role of Nuclear Respiratory Factor 1 in Regulating both Cytochrome c Oxidase and NMDA Glutamate Receptor Subunit Genes: "Dhar, S. S. and Wong-Riley, M. T. T. (2009). Coupling of energy metabolism and synaptic transmission at the transcriptional level: Role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and nmda glutamate receptor subunit genes. J. Neurosci., 29(2):483-492."
Yonden, Z., Aydin, M., Kilbas, A., Demirin, H., Sutcu, R., and Delibas, N. (2010). Effects of ammonia and allopurinol on rat hippocampal nmda receptors. Cell biochemistry and function. http://www.citeulike.org/user/HEIRS/article/6567065
Pall, Martin.  (2007). Explaining Ünexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479

Study shows correlation between mitochondrial biogenesis and G6PDH

Recent study shows correlation between G6PDH and mtDNA replication. This
may account for low developmental competance in these animals. Marker changes
include those for COX1, NRF1 and tFAM.

CiteULike: Transcript expression of mitochondria related genes is correlated with bovine oocyte selection by BCB test.: "Opiela, J., Lipiński, D., Słomski, R., and Katska-Ksiazkiewicz, L. (2010). Transcript expression of mitochondria related genes is correlated with bovine oocyte selection by bcb test. Animal reproduction science, 118(2-4):188-193."

Parkinsons Model Identifies Protein & Mitochondria Metabolic Dysruptions

In Parkinson's disease model, while oxygen consumption is similar to control lines, PD lines demonstrate reduced SIRT1 phosphorylation, lower PGC-1a levels and increased NF-kabbaB activation. Results suggest altered aerobic metabolism and mitochondrial respiration.

Mitochondrial Respiration and Respiration Associated Proteins in Cell Lines Created through Parkinson's Subject Mitochondrial Transfer.: "Raquel Esteves, A., Lu, J., Rodova, M., Onyango, I., Lezi, E., Dubinsky, R., Lyons, K. E., Pahwa, R., Burns, J. M., Cardoso, S. M., and Swerdlow, R. H. (2010). Mitochondrial respiration and respiration associated proteins in cell lines created through parkinson's subject mitochondrial transfer. Journal of neurochemistry."

Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

PGC-1a a protein factor necessary for mitochondrial function and may be reduced with exposure to LPS as well as, from impairments in Nrf2. This study demonstrates that TNF-a (already identified as a factor in CFS and Parkinson's) is generated from exposure to cigarette smoke (and lots of other environmental contaminants) and has been shown to down-regulate PGC-1a that may lead to vascular and myocyte dysfunction. PGC-1a also regulates a number of glucose transporters such as GLUT1 and GLUT4 which trasport glucose into cells.  When one looks at a condition related to glucose uptake from impairment of glucose transporters such as in GLUT1 deficiency, there are recognizable patterns of impairment one may recognize in other environmental illnesses including CFS and fibromyalgia and also described as Parkinsonism and ataxia-like symptoms.  Because Nrf2 contributes to PGC-1a expression, a deficiency in Nrf2 may also present with these types of symptoms impaired after cigarette exposure and particulate matter from diesel exhaust. Of course, other factors such as accumulation of ammonia and genetic SNP may also pose potential cellular threats. PGC-1a can be increased through exercise but this will be dependant on the availabity of NRF1 (another protein) regulated by Nrf2/HO-1. Sauna and Waon therapy have been shown to elevate PGC-1a and Nrf2. Deficiencies of PGC-1a may exacerbate the autoimmune-type presentation of environmental illness in Nrf2 deficiencies which produce less HO-1. Lack of PGC-1a and Nrf2 may contribute to the development of chronic diabetes in addition to other metabolic complications and numerous other conditions, such as cardiovascular disease.


For review:

• Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!
• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

CiteULike: TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.: "Tang, K., Wagner, P. D., and Breen, E. C. (2010). Tnf-alpha-mediated reduction in pgc-1alpha may impair skeletal muscle function after cigarette smoke exposure. Journal of cellular physiology, 222(2):320-327."





Lihua CHE, N. and Chiwai WON, G. Estrogen-related receptor a inverse agonist enhances basal glucose uptake in myotubes through reactive oxygen species. Biological Pharmacology Bulletin, 32(7):1199-1203. http://www.citeulike.org/user/HEIRS/article/6512026
Arany, Z., Foo, S.-Y. Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H. H., Rosenzweig, A., and Spiegelman, B. M. (2008). Hif-independent regulation of vegf and angiogenesis by the transcriptional coactivator pgc-1alpha. Nature, 451(7181):1008-1012. http://www.citeulike.org/user/HEIRS/article/2406298
Pons, R., Collins, A., Rotstein, M., Engelstad, K., and De Vivo, D. C. (2009). The spectrum of movement disorders in glut-1 deficiency. Movement Disorders, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6512017
Piantadosi, C. A., Carraway, M. S., Babiker, A., and Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res, 103(11):1232-1240. http://www.citeulike.org/user/HEIRS/article/4617070?show_msg=already_posted
Glucose Transporter. Wipedia. Retrieved January 10, 2009.

Cybrid models of parkinson's disease show variable mitochondrial biogenesis and genotype-respiration relationships

Keeney, P. M., Dunham, L. D., Quigley, C. K., Morton, S. L., Bergquist, K. E., and Bennett, J. P. (2009). Cybrid models of parkinson's disease show variable mitochondrial biogenesis and genotype-respiration relationships. Experimental neurology, 220(2):374-382. http://www.citeulike.org/user/HEIRS/article/5913095

Pgc-1β: A regulator of mitochondrial function with subtle roles in energy metabolism

"As expected from PGC-1β’s ability to stimulate mitochondrial function, the loss of PGC-1β decreased the transcription of genes encoding many of the mitochondrial proteins that generate ATP and heat. Yet the mutant mice appeared essentially healthy under normal conditions. Still, a slight impairment of mitochondrial function might lead to some metabolic imbalance, for instance obesity, since mitochondria burn energy that would otherwise be stored as fat."

Chanut, F. (2006). Pgc-1β: A regulator of mitochondrial function with subtle roles in energy metabolism. PLoS Biol, 4(11):e402+. http://www.citeulike.org/user/HEIRS/article/6016816

PGC-1a , Cold, MCK, Myogenesis and Nrf2 and Environmental Illness?!

Background: Chronic fatigue syndrome has been shown in a study to have fast-twitch muscle fibers and cold sensitivity is a common complaint in patients with CFS. Mitochondrial biogenesis is dependant on a transcription protein that interacts with other proteins in mitochondrial synthesis. PGC-1a activity directly effects the number and density of mitochondria. Different tissues have different levels of mitochondria.
Other studies have shown that increasing the number of mitochondria may result in longer lifespan and improved quality of life. In mice, increasing the number of mitochondria can improve muscle weakness and increase survival.  With more mitochondria, mice lived longer without symptoms.

"The essential role of PGC-1 in adaptive thermogenesis is convincingly demonstrated by the observation that the PGC-1-deficient mice are unable to withstand a cold stress (4°C) for longer than 6 h due to a continuous decrease of core body temperature. Wild-type control mice, on the other hand, were able to tolerate the cold stress by keeping their core body temperature at 36.5°C, after an initial drop of 1.5°C.".....

Pietrangelo explains from his study that "fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Lane showed several years ago that patients with lactate responses to exercise also exhibited a lower proportion of mitochondrial-rich fiber type. Liang explains that "skeletal muscle fibers are classified into three types: type I, type IIa, and type IIb. Slow-twitch type I and fast-twitch type IIa fibers contain more mitochondria and exhibit relatively higher rates of oxidative metabolism. In contrast, type IIb fibers have fewer mitochondria and are metabolically glycolytic. It is now well established that PGC-1 induces a remodeling of skeletal muscle fiber composition. In general, the ratio of glycolytic type IIb fibers to the more oxidative type I and type IIa fibers decreases. The expression of PGC-1 in skeletal muscle is readily inducible by both short-term exercise and endurance training in rodent models and human subjects. Our understanding of the biological role of PGC-1 in skeletal muscle structure and function has been greatly improved through the use of gain of function and loss of function mouse models. In a gain of function transgenic model, PGC-1 is overexpressed in a skeletal muscle-specific manner under the control of the muscle creatine kinase (MCK) promoter. PGC-1 overexpression results in the conversion of fast-twitch type IIb muscle fibers to type IIa and slow-twitch type I fibers by 20% and 10%, respectively, in plantaris muscle." Handchin explains the mice with an absence of PGC-1a in muscle present with an increase inflammatory cytokines including Tnf-a and IL-6 and that heterozygous animals produce smaller but significant increases in these cytokines. This provides evidence that inflammation, he says, is originating from the muscles themselves. A drop in PGC-1a expression in heterozygoes is similar to that of patients with a 36% drop in PGC-1a in diabetic patients which also corresponds to a PGC-1a drop in active vs. non-active animals. He says also that while one can not make a causality connection between PGC-1a and pro-inflammatory genes is not possible in humans, the patients do exhibit an increase in Tnf-a and Il-6 in muscle and Il-6 in serum. The reduction of PGC-1a mRNA in diabetic Type 2 patients is likely linked to a chronic state of low-grade inflammation." (Handchin)


Ding shows that "Nrf2 suppression blocks myogenesis. The knockdown of Nrf2 by siRNA transfection blocked the expression of myogenin and MHC, as well as morphological changes in myotube formation. We also verified these results via MCK-dependent luciferase assay using the MCK-responsive luciferase reporter plasmid, MCK-Luc. The knockdown of Nrf2 reduced MCK promoter activity, when measured 48 hours after the induction of differentiation." He also demonstrated that H2O2 signals are important for signaling and induction of GSH and the GSH/GSSH during muscle differentiation via Nrf2/GCL/GR/GSH signal pathway.



I can not provide all the citation below as it is in Japanese or Chinese.
Liang, H. and Ward, W. F. (2008). Pgc-1: a key regulator of energy metabolism. http://www.citeulike.org/user/HEIRS/article/5805611
Ding, Y., Choi, K. J., Kim, J. H., Han, X., Piao, Y., Jeong, J.-H., Choe, W., Kang, I., Ha, J., Forman, H. J., Lee, J., Yoon, K.-S., and Kim, S. S. (2008). Endogenous hydrogen peroxide regulates glutathione redox via nuclear factor erythroid 2-related factor 2 downstream of phosphatidylinositol 3-kinase during muscle differentiation. Am J Pathol, 172(6):1529-1541. http://www.citeulike.org/user/HEIRS/article/3481324
New Hope For Treating Common Form Of Inherited Neuromuscular Disease. Medical News Today.
Lane, R. J., Barrett, M. C., Woodrow, D., Moss, J., Fletcher, R., and Archard, L. C. (1998). Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. Journal of neurology, neurosurgery, and psychiatry, 64(3):362-367. http://www.citeulike.org/user/HEIRS/article/3578915
Pietrangelo, T., Toniolo, L., Paoli, A., Fulle, S., Puglielli, C., Fan X00f2, G., and Reggiani, C. (2009). Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study. International journal of immunopathology and pharmacology, 22(2):427-436. http://www.citeulike.org/user/HEIRS/article/4812216
Handschin, C. and Spiegelman, B. M. (2008). The role of exercise and pgc1alpha in inflammation and chronic disease. Nature, 454(7203):463-469. http://www.citeulike.org/user/HEIRS/article/3038457

Freeze-Dried Grape Powder Attenuates Mitochondria- and Oxidative Stress-Mediated Apoptosis in Liver Cells

HMM - so where does one get this...?
Freeze-Dried Grape Powder Attenuates Mitochondria- and Oxidative Stress-Mediated Apoptosis in Liver Cells

High Fat Diets Make One More Susceptible to Oxidative Stress and Environmental Illness!

Background:

• Obesity is also an important risk factor for a number of health conditions including diabetes and cardiovascular disease.
• Fatty liver disease is a condition where large amounts of fat accumulate in liver cells and is characteristic of metabolic syndrome. (Wipedia)

High fat diets decrease PGC-1a which is important for metabolic cellular processes, mitochondrial biogenesis and mitochondrial DNA synthesis. In addition, it decreases the expression of Nrf2 which is the master gene promoter that upregulates expression of genes important for the same process. The PGC-1a complex also controls another protein called Foxo3a which is an important modulator of aging. (Dong)

In addition to playing a role in redox homeostasis, Nrf2 modulates inflammatory mediators such as Tnf-a and MCP-1 and prevents lipid accumulation. Nrf2 is activated in response to toxicant injury and oxidative stress and is important for the detoxification of xenobiotics.
Tanaka's studies have shown the absence of Nrf2 increases susceptibility to toxicants including acetaminophen, hyperoxia, benzopyrene (found in smoke). He demonstrated that Nrf2 has important lipid metabolism and that feeding a high fat diet in the short term reduces Nrf2. He notes, other studies have shown long-term feeding of high fat diets increases Nrf2 and suggests this is an adapative response to oxidative stress induced by chronic fat accumulation. Generally, animals with lower Nrf2 present with elevated cholesterol levels and lower levels of Nrf2 results in the inability to prevent lipid accumulation, absence leads to greater retention of lipids in the liver (fatty liver disease) and greater oxidative stress including, oxidative stress in the mitochondria and the endoplasmic reticulum. Interestingly, Tanaka found that PGC-1a is reduced in high-fat diets but not in Nrf2 null mice which indicates the down-regulation of PGC-1a is dependant on Nrf2.

Summary: High fat diets reduce mitochondrial biogenesis, increases the likelihood for toxicant bioaccumulation and their overall toxic effects, increases oxidative stress, contributes to fat accumulation and obesity and impairs liver function which is an important organ for detoxification.

Dong, F., Li, Q., Sreejayan, N., Nunn, J. M., and Ren, J. (2007). Metallothionein prevents high-fat diet–induced cardiac contractile dysfunction role of peroxisome proliferator–activated receptor
coactivator 1 and mitochondrial biogenesis. 56(9):2201-2212. http://www.citeulike.org/user/HEIRS/article/5724999
Tanaka, Y., Aleksunes, L. M., Yeager, R. L., Gyamfi, M. A., Esterly, N., Guo, G. L., and Klaassen, C. D. (2008). Nf-e2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther, 325(2):655-664. http://www.citeulike.org/user/HEIRS/article/4788030

Angiotensin, CAMKII and ROS

HEIRS Environmental Illness Research Blog: Fibromyalgia, Endoplasmic Reticulum Stress, Neurotoxicity and CAMKII

Activation of the angiotensin system which may lead to generation of NADPH oxidase and ROS. The NADPH oxidase system is the major source of ROS generation from angiotensin and exaggerates ROS production from the mitochondria. Li demonstrates that angiotensin stimulates CAMKII, H2O2 production release of arachidonic acid and subsequent Akt activation induced by phospholipase 2.

Zhang, G.-X. X., Lu, X.-M. M., Kimura, S., and Nishiyama, A. (2007). Role of mitochondria in angiotensin ii-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc Res. http://www.citeulike.org/user/HEIRS/article/1643746
Li, F. and Malik, K. U. (2005). Angiotensin ii-induced akt activation is mediated by metabolites of arachidonic acid generated by camkii-stimulated ca2+-dependent phospholipase a2. Am J Physiol Heart Circ Physiol, 288(5):H2306-2316. http://www.citeulike.org/user/HEIRS/article/4626324

Mitochondrial Bioenergetics, CFS, Muscle Fatigue, PGC-1a, CAMKII and Nrf2.

Chronic fatigue syndrome is a condition that includes overwhelming fatigue even with rest that lasts for a period of six months or longer. It has been 3 decades since research on the condition began and there is no definitive answer on what causes it. However, they are making research strides and have an idea of at least some things that may contribute to it. SIRT1 activity regulates most of its activity through PGC-1a which an important regulator of metabolic homeotstasis, cellular function and mitochondrial biogenesis. Generally, cells that are lacking in PGC-1a are more insulin resistant and also have less eNOS.

In chronic fatigue syndrome, patients have a slow to fast twitch muscular presentation and altered muscle metabolism. (Pietrangelo) CAMKII is also important in fast-twitch muscle for sustaining contraction during exercise and it has been demonstrated that lower levels of CAMKII which are common in mitochondrial respiratory deficiencies may effect muscle performance. (Tanaka) AMPK is also another important regulator of this pathway through phosporylation of PGC-1a (Jager). AMPK also improves fatty acid metabolism in muscle and that activity is partially dependant on CAMKII (Rose). Again, a decrease in CAMKII would surely lead to changes in muscle metabolism. In this case, poor fatty acid metabolism causes higher fat in the muscle and is associated with insulin resistance and obesity and potentially, diabetes. (Adams) Interestingly, 89% of the muscles around the eyes and certain other areas of the face are fast-twitch muscles which may contribute to certain types of facial pain. Fast twitch muscle have less PGC-1a and as a result mitochondrial content is decreased and muscle activity is “energetically less efficient and expensive”(Schaffer). Cells with higher levels of PGC-1a have a better recovery of mitochondrial function to oxidant stress than those with lower levels of PGC-1a. (Rasbach) This would suggest a down-regulation or inhibition of SIRT1 activity which can be inhibited by many factors including nutrition including excessive calorie intake, Tnf-a or overproduction of H2O2. Many exposures including those to dioxin can increase levels of the pro-inflammatory Tnf-a (Frigo). Overall, cells with negative alterations in PGC-1a have demonstrated metabolic abnormalities, are more sensitive to cold, have more degenerative lesions and when expoxed to H2O2 are more apt to become damaged.

Because Nrf2 regulates NRF1 which is intricately tied and necessary for PGC-1a cellular function, Nrf2 becomes an important part of the pathway of SIRT1 and PGC-1a. Piantadosi describes the process as ”Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3 (GSK3b), which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter.” (Piantadosi) In simple terms, GSK3b can become an on/off switch for Nrf2 and you got to have the promoter nuclear respiratory factor NRF-1 and Nrf2. In terms of mitochondrial function, it seems like the NRF-1/Nrf2 complex would be an important place where future therapies target. One already in existence that provides some of this action is metformin which is used as a diabetes treatment. Exercise may increase levels of PGC-1a but this is inhibited in insulin resistant muscle.(Filippis) Resveratrol and quercetin may improve mitochondrial function.


Notes:
****Nrf2 SNPS can be ethnically-derived which would make people with more (or less) susceptible to oxidative stress and possibly a decrease in mitochondrial biogenesis. (Marzec)
****SNPs or mutations may make Nrf2 less responsive or overly responsive to cell signals.
****Friedrich's Ataxia is a condition caused by an alteration in coding for Nrf2 which leads to poor induction of the antioxidant system. It is not the only form of ataxia. Read more about ataxia here. Other SNPs may cause one to be more sensitive to lung injury. Some of the symptoms may seem similar to those with some symptoms related to chemical sensitivity.

****The Nrf2 regulates a number of proteins including the aryl hydrocarbon which may be an important initiator and factor in multiple chemical sensitivity. The AhR is responsible for mediating the detoxification of PAHs and HAHs in addition to other xenobiotics. It has also been determined it mediates most of the toxicity associated with dioxins.


This is a list of common symptoms associated with CFS:
*cognitive dysfunction, including impaired memory or concentration
*postexertional malaise lasting more than 24 hours (exhaustion and increased symptoms) following physical or mental exercise
*unrefreshing sleep
*joint pain (without redness or swelling)
*persistent muscle pain
*headaches of a new type or severity
*tender cervical or axillary lymph nodes
*sore throat

Other Common Conditions:
*irritable bowel, abdominal pain, nausea, diarrhea or bloating
*chills and night sweats
*brain fog
*chest pain
*shortness of breath
*chronic cough
*visual disturbances (blurring, sensitivity to light, eye pain or dry eyes)
*allergies or sensitivities to foods, alcohol, odors, chemicals, medications or noise
*difficulty maintaining upright position (orthostatic instability, irregular heartbeat, dizziness, balance problems or fainting)
*psychological problems (depression, irritability, mood swings, anxiety, panic attacks)
*jaw pain
*weight loss or gain

Source: CDC

Citations: Original Post Source
****