Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and by disease processes.

CiteULike: Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and by disease processes.: "the emerging importance of master regulators of antioxidant defences such as Nrf2 and PGC-1α is revealing ways by which intrinsic defences may be manipulated to combat oxidative/nitrosative stress."

IDENTIFICATION OF THE ARYL HYDROCARBON RECEPTOR TA... [J Biol Chem. 2010] - PubMed result

IDENTIFICATION OF THE ARYL HYDROCARBON RECEPTOR TA... [J Biol Chem. 2010] - PubMed result: "The vitamin B3 constituent, nicotinamide (NAM), prevented TCDD suppression of glucose output, NAD(+), and gluconeogenic genes and stabilized PGC1α. The corrective effects of NAM could be attributed to increased NAD(+) levels and suppression of AHR target gene induction."

Positive correlation between PPAR{gamma}/PGC-1{alp... [Acta Biochim Biophys Sin (Shanghai). 2010] - PubMed result

Comment: Recent studies suggest Nrf2 may regulate to PPAR-gamma to a degree.

"activation of the PPARgamma/PGC-1alpha pathway may protect against COPD progression by upregulating gamma-GCS and relieving oxidative stress."

Read more: Positive correlation between PPAR{gamma}/PGC-1{alp... [Acta Biochim Biophys Sin (Shanghai). 2010] - PubMed result:

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"

Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: Roles of PPARgamma and Th2 cytokines.

CiteULike: Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: Roles of PPARgamma and Th2 cytokines.: "we propose that exercise-induced PPARgamma/PGC-1(alpha/beta)-mediated M2 polarisation may constitute a novel anti-inflammatory benefit of low-intensity exercise."

Food Molds: Does Impairment of PGC-1a Contribute to Their Toxicity?

Background: PGC-1a is an important regulator of metabolism in different tissues including the muscle and liver and its expression may be of important significance in a variety of diseases including neurodegenerative diseases and diabetes and influences circadian rythyms.  In addition, its activities are directly influenced by a number of other proteins including AMPK and SIRT1.

Vomitoxin, also known as deoxynivalenol (DON) is a  mycotoxin found in different types of foodstuffs and can be associated with mycotoxicosis in both animals and humans.While its negative health effects are generally milder than other mycotoxins susceptible populations could be more at risk. Generally, this class of mycotoxins are proteins inhibitors and may alter expression of neurotransmitters such as serotonin which can lead to weight loss because of the anorexic effects of elevations of serotonin.  These changes may also influence normal activity of the respiratory tract. (Wipedia) According to a recent study and in-line with the DON's ability to negative influence protein expression, DON has been demonstrated to upregulate a known of repressor of PGC-1a in addition to other proteins.  This could explain why individuals ( or animals) with impaired antioxidant and immune systems, metabolic dysfunctions, or the aged may show more health effcts upon mold exposure. 


Osman, A. M., Pennings, J. L., Blokland, M., Peijnenburg, A., and van Loveren, H. (2010). Protein expression profiling of mouse thymoma cells upon exposure to the trichothecene deoxynivalenol (don): implications for its mechanism of action. Journal of immunotoxicology, 7(3):147-156. http://www.citeulike.org/user/HEIRS/article/7607619




Leone, T. C., Lehman, J. J., Finck, B. N., Schaeffer, P. J., Wende, A. R., Boudina, S., Courtois, M., Wozniak, D. F., Sambandam, N., Bernal-Mizrachi, C., Chen, Z., Holloszy, Medeiros, D. M., Schmidt, R. E., Saffitz, J. E., Abel, E. D., Semenkovich, C. F., and Kelly, D. P. (2005). Pgc-1α deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol, 3(4):e101+.  http://www.citeulike.org/user/HEIRS/article/2909101?show_msg=already_posted

Inactivation of Foxo3a and Subsequent Downregulation of PGC-1alpha Mediate Nitric Oxide-Induced Endothelial Cell Migration.

Background: FOXO3a is a protein that is an important regulator of oxidative stress by modulating antioxidants like catalase, influences aging, is a tumor repressor, reduced in Nrf2 animals and may contribute to fertility problems. It is found in higher amounts in centenarians, meaning those that live to a hundred years or more. Its activity can be effected by methylation and acetylation. (Wipedia-FOXO3a)

"Borniquel, S., García-Quintáns, N., Valle, I., Olmos, Y., Wild, B., Martínez-Granero, F., Soria, E., Lamas, S., and Monsalve, M. (2010). Inactivation of foxo3a and subsequent downregulation of pgc-1alpha mediate nitric oxide-induced endothelial cell migration. Molecular and cellular biology, 30(16):4035-4044."

CiteULike: Inactivation of Foxo3a and Subsequent Downregulation of PGC-1alpha Mediate Nitric Oxide-Induced Endothelial Cell Migration.:

PGC-1alpha is required for AICAR induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle.

CiteULike: PGC-1alpha is required for AICAR induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle.: "provide genetic evidence for a major role of PGC-1alpha in AMPK mediated regulation of mitochondrial and glucose membrane transport protein expression in skeletal muscle."

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]

PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload

"This data indicates that PGC-1α plays an important role in regulating expression of myocardial mitochondrial antioxidants SOD2 and Trx2 and in protecting hearts against TAC-induced myocardial oxidative stress, hypertrophy, and dysfunction."

"Lu, Z., Xu, X., Hu, X., Fassett, J., Zhu, G., Tao, Y., Li, J., Huang, Y., Zhang, P., Zhao, B., and Chen, Y. (2010). Pgc-1α regulates expression of myocardial mitochondrial antioxidants and myocardial oxidative stress after chronic systolic overload. Antioxidants and Redox Signaling."

Read more: CiteULike: PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload:

PGC-1a, PGc-1b Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy

"PGC-1α and PGC-1β to inhibit FoxO3 and NFκB actions and proteolysis helps explain how exercise prevents muscle atrophy."

CiteULike: Peroxisome Proliferator-activated Receptor γ Coactivator 1α or 1β Overexpression Inhibits Muscle Protein Degradation, Induction of Ubiquitin Ligases, and Disuse Atrophy:

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

PGC-1a Improves Lipid Use, Insulin Signalling and Glucose Transport in Muscle.

"Increases in PGC-1α levels, similar to those that can be induced by physiological stimuli, altered intramuscular lipids and improved fatty acid oxidation, insulin signalling and insulin-stimulated glucose transport, albeit to different extents in lean and insulin-resistant muscle."


CiteULike: Increased levels of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α) improve lipid utilisation, insulin signalling and glucose transport in skeletal muscle of lean and insulin-resistant obese Zucker rats:

PGC-1a and Exercise and Impact on Muscle Function and Insulin Sensitivity

"modest (~25%) upregulation of PGC-1alpha, within physiologic limits, does improve mitochondrial biogenesis, fatty acid oxidation and insulin sensitivity in healthy and insulin resistant skeletal muscle."

PGC-1{alpha} REGULATION BY EXERCISE TRAINING AND AND ITS INFLUENCES ON MUSCLE FUNCTION AND INSULIN SENSITIVITY [Am J Physiol Endocrinol Metab. 2010] - PubMed result:

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- ?

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

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissuesand endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.

HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine


HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,

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Original Article and Citations:

Interdependence of AMPK and SIRT1 for Metabolic Adaptation to Fasting and Exercise in Skeletal Muscle.

"Here we demonstrate that AMPK acts as the prime initial sensor that translates this information into SIRT1-dependent deacetylation of the transcriptional regulators PGC-1alpha and FOXO1, culminating in the transcriptional modulation of mitochondrial and lipid utilization genes. Deficient AMPK activity compromises SIRT1-dependent responses to exercise and fasting, resulting in impaired PGC-1alpha deacetylation and blunted induction of mitochondrial gene expression."

Interdependence of AMPK and SIRT1 for Metabolic Adaptation to Fasting and Exercise in Skeletal Muscle.

Impaired Liver Glucose Production in a Murine Model of Steatosis and Endotoxemia: Protection by Inducible Nitric Oxide Synthase

Comparison between wild-type and iNOS-knockout mice under these conditions demonstrated a protective role of iNOS against fatal hypoglycemia. Nitric oxide (NO) signaling effects were confirmed by treatment of hepatocytes in culture with an NO donor, which resulted in increased expression of PGC-1α and gluconeogenic genes.

CiteULike: Impaired Liver Glucose Production in a Murine Model of Steatosis and Endotoxemia: Protection by Inducible Nitric Oxide Synthase: "Tirosh, O., Artan, A., Aharoni-Simon, M., Ramadori, G., and Madar, Z. (2010). Impaired liver glucose production in a murine model of steatosis and endotoxemia: Protection by inducible nitric oxide synthase. Antioxidants and Redox Signaling."

Parkinson's and Link To Muscle Protein and Cell Signaling Pathway?

I recently noted that transcription factors such as MEF2, NRF1, NRF2 are co-activated by PGC-1a (important for mitochondrial biogenesis) results in kind of a loop to increase the expression of PGC-1a. PGC-1a regulates a number of transporters that regulate chemicals across membranes and alterations in these proteins may increase or lead to tissue dysfunction.

Recent evidence indicates that chaperone-mediated autophagy plays a role in direct degradation of neuronal transcription factor MEF2D, a protein known to promote neuronal survival. Disruption of this regulatory pathway by α-synuclein leads to neuronal stress, which may underlie neuronal loss in Parkinson’s disease.

For further reading:

• Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness
• Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1
• Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1 -- Piantadosi et al. 103 (11): 1232 Figure IG7 -- Circulation Research
• Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

Yang, Q. and Mao, Z. (2010). Dysregulation of autophagy and parkinson's disease: the mef2d link. Apoptosis. http://www.citeulike.org/user/HEIRS/article/6715832
Wright, D. C., Han, D.-H. H., Garcia-Roves, P. M., Geiger, P. C., Jones, T. E., and Holloszy, J. O. (2007). Exercise-induced mitochondrial biogenesis begins before the increase in muscle pgc-1alpha expression. The Journal of biological chemistry, 282(1):194-199. http://www.citeulike.org/user/HEIRS/article/6580001
Brockmann, K., Wang, D., Korenke, C. G., Von Moers, A., Ho, Y.-Y., Pascual, J. M., Kuang, K., Yang, H., Ma, L., Kranz-Eble, P., Fischbarg, J., Hanefeld, F., and De Vivo, D. C. (2001). Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Annals of Neurology, 50(4):476-485. http://www.citeulike.org/user/HEIRS/article/6715941
Hernandez, M. J., Roberts, T. M., and Hardin, C. D. (2007). Caveolin-1 and the organization of glycolysis in astrocytes: Modulation by ammonia. The FASEB Journal, 21. http://www.citeulike.org/user/HEIRS/article/6715979
Klinge, C. M. (2008). Estrogenic control of mitochondrial function and biogenesis. Journal of Cellular Biochemistry, 105(6):1342-1351. http://www.citeulike.org/user/HEIRS/article/3879108