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Showing posts with label PGC-1α. Show all posts
Showing posts with label PGC-1α. Show all posts

Wednesday, 16 October 2019

DMF for Mitochondrial Dysfunction in Autism and Friedreich's Ataxia?


Yet more money was just donated to autism research. In 2017 the CEO of Broadcom gave $20 million to MIT and now he has given $20 million to Harvard, where he did his MBA.




Time to boost Homer's mitochondria?


I think philanthropists from the fast-moving IT sector should demand rather more from the slow-moving world of autism research.  I also think common sense is often more lacking than money.

The US Government has also just announced $1.8 billion for autism research.

Donald Trump authorized a five-year extension of the Autism Collaboration, Accountability, Research, Education and Support (CARES) Act. The 2014 act dedicated funds to children with autism spectrum disorder, but the new version includes adults.  Children with autism do indeed grow up to become adults with autism. 
Today we look at further applications of DMF, which is a cheap chemical also sold as a very expensive drug.

We learnt from Dr Kelley, from Johns Hopkins, that most regressive autism features mitochondrial dysfunction. Mitochondria within cells produce ATP (fuel) via a complex multi-step process called OXPHOS. If you lack any of the required enzyme complexes for OXPHOS, that part of your body will suffer a power shortage/outage.  Another potential problem is just too few mitochondria.

The treatment for mitochondrial disease is mainly to avoid further damage, using antioxidants.  If you know which enzyme complex is lacking, you might try and target that.

We saw a long time ago in this blog that PGC-1α is the master regulator of mitochondrial biogenesis and as such this would be a target for people with mitochondrial dysfunction.

Among other interactions, PGC-1α is affected by something called PPAR-γ (Peroxisome proliferator-activated receptor gamma), also known as the glitazone receptor.

There are many cheap drugs that target PPAR-γ, because this is also one way to treat type 2 diabetes.  We saw that Glitazone drugs have been successfully trialed in autism.

Today we look at another way to activate PGC-1α and stimulate the production of more mitochondria and increase the necessary enzyme complexes for OXPHOS.

Many people with autism in the US are diagnosed by their MAPS/DAN doctor as lacking Complex 1.

DMF has two principal effects. It affects NRF2 and HCAR2.

Many supplements sold online are supposed to activate NRF2, but may well lack potency.

Activating NRF2 turns on your antioxidant defences and so is good for people with autism, diabetes, COPD and many other conditions, but is bad for someone with cancer.

We will see later how, somewhat bizarrely, at high doses DMF reverses function and causes cell death via oxidative stress, making it a potent potential cancer therapy.  Cancer cells are highly vulnerable to oxidative stress.

In this blog we are focusing on low doses of DMF, that are NRF2 activating.

In the chart below the NFE2L2 gene encodes the transcription factor NRF2. We want the antioxidant genes turned on.

We then get another benefit because NRF2 expression also regulates NRF1 expression.

The transcription factor NRF1 is another regulator of mitochondrial biogenesis with involvements in mitochondrial replication  and transcription of mitochondrial DNA.

We then get a third benefit from DMF via activating HCAR2, this time we increase Complex I expression.  In the OXPOS multistep process to make fuel/ATP the bottleneck is usually Complex I, so Complex I is often referred to as being “rate limiting”. Complex I is the most important deficiency to fix.









Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans



The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.

                                                                                                                    
DMF for Friedreich's ataxia

Friedreich's ataxia (FA) is a genetic disease caused by mutations in the FXN gene on the chromosome 9, which produces a protein called frataxin. It causes difficulty walking, a loss of sensation in the arms and legs and impaired speech that worsens over time. Symptoms typically start between 5 and 15 years of age. Most young people diagnosed with FA require a mobility aid such as a wheelchair by their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes.

Frataxin is required for the normal functioning of mitochondria, the energy-producing factories of cells. Mutations in the FXN gene lead to a decrease in the production of frataxin and the consequent disruption in mitochondrial function.
No effective treatment exists. FA shortens life expectancy due to heart disease, but some people can live into their sixties.


Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.


High Dose DMF to treat some cancer

Some readers may recall that the protein DJ-1 is encoded by the Parkinson’s gene PARK7 and that DMF has already been proposed as a therapy for Parkinson’s disease. 

At high doses of DMF the protein DJ-1 loses its stabilization function and ends up effectively blocking NRF2. Put simply, high dose DMF turns off NRF2, making it a cancer cell killer.

Dimethyl Fumarate Controls the NRF2/DJ-1Axis in Cancer Cells: Therapeutic Applications

The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in noncancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (<25 a="" activation="" antioxidant="" cytoprotective="" dmf="" has="" mol="" nrf2="" of="" pathway.="" role="" span="" the="" through=""> At higher concentrations, however (>25 μmol/L), DMF caused oxidative stress and subsequently cytotoxicity in several cancer cell lines. High DMF concentration decreases nuclear translocation of NRF2 and production of its downstream targets. The pro-oxidative and cytotoxic effects of high concentration of DMF were abrogated by overexpression of NRF2 in OVCAR3 cells, suggesting that DMF cytotoxicity is dependent of NRF2 depletion. High concentrations of DMF decreased the expression of DJ-1, a NRF2 protein stabilizer. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antioxidant defenses, and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed in vivo in two mice models of colon cancer. Taken together, these findings implicate the effect of DJ-1 on NRF2 in cancer development and identify DMF as a dose-dependent modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants.







Proposed mechanism of DMF-induced cancer cell death. Low concentrations of DMF can induce the NRF2 antioxidant pathway, allowing NRF2 nuclear translocation and binding to the antioxidant response elements leading to the transcription of antioxidant and detoxifying enzymes, thereby promoting cell survival. High concentrations of DMF, however, induce disruption of the NRF2 stabilizer DJ-1, which in turn impairs NRF2 induction and transcriptional activities in response to DMF, induces ROS generation, GSH depletion, and hence, facilitates cancer cell death. Cys, cysteine; 2SC, succination of cysteine residues.


Conclusion

This post did not cost $20 million, it is yours for free.

It looks pretty obvious that people with autism caused by, or associated with, mitochondrial dysfunction might potentially benefit from DMF.

People with Friedreich’s Ataxia do not currently have any treatment options. Low dose DMF is free of side effects, the high doses used to treat Psoriasis and Multiple Sclerosis often cause troubling GI side effects.

DMF seems to have very many potential therapeutic applications, limited only by the cost of the pharmaceutical version of this cheap chemical. Fortunately the "autism dose" is tiny.


Related Earlier Posts







Monday, 8 May 2017

Pan-agonists of PPARs and PGC-1α in Mitochondrial Disease, Autism and Sport


Today’s post should be of interest to those concerned about mitochondrial disease and mTOR.


mTOR is a very important signaling cascade that often dysfunctional in autism. Many aspects of autism and its comorbidities can be traced back to mTOR.
The going is easier with a PPAR pan-agonist 

mTOR integrates the input from upstream pathways, including insulin, growth, and amino acids.   mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, certain cancers and indeed autism.

One important process affected by mTOR is the creation of new mitochondria in your cells.  Each cell has many mitochondria, but in some people there are not enough and/or they may not work properly.  
In the above post we saw that Oxidative phosphorylation (or OXPHOS in short) is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy.  This takes place inside mitochondria.

The five enzymes required have simplified names: complex I, complex II, complex III, complex IV, and complex V.

The most common problem in autism is a lack of complex 1, this leads to a lack in the production of energy (ATP) in cells.  In your muscles this will appear as a lack of exercise endurance and in your brain as a lack of cognitive function.

On that rather intimidating chart (below), all about mTOR, tucked away at the bottom right is PGC-1α.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the master regulator of mitochondrial biogenesis.

PGC-1α may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a many factors, including:-


·         Exercise  (gradual endurance training)


·         PPARδ , PPARγ and it was thought PPARα


·         AMPK (Metformin, or AICAR)


·         Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Interestingly, massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. Many autism parents believe in various massage therapies. 

Metformin is a very old drug to treat diabetes, it does activate AMPK but unfortunately it also inhibits the Complex 1 mitochondrial enzyme. This might explain why one reader of this blog found it had a negative effect in her son.  In some types of cancer metformin can be used to “starve” the cancer cells of energy and stop them proliferating.

AICAR was thought to have been used by cyclists in the 2009 Tour de France, it is a heart drug from the 1980s. It activates AMPK and increases nitric oxide production from endothelial nitric oxide synthase.













Here is the lower right part enlarged:-





  

The above chart, while complex does not give the complete picture regarding PPAR.

It appears that the type of PPAR that is needed to activate PGC-1α  is actually PPARδ  (PPAR delta). For a long time researchers thought it was PPAR α (PPAR alpha).


PGC-1 alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1 alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPAR delta but not PPAR alpha underlies this effect. PPAR delta induces PGC-1 alpha gene transcription through a PPAR-response element in the PGC-1 alpha promoter. Moreover, PGC-1 alpha coactivates the PPAR delta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPAR6 expression by PGC-1 alpha. These data point to a distinct value of PPARdelta rather than PPAR alpha agonists in the improvement of oxidative metabolism in muscle.



Peroxisome proliferator-activated receptors (PPARs)

There was a post in this blog a long time ago about all the PPARs. There are three types (alpha, delta and gamma) just to confuse us, sometimes delta is called beta.

  • α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
  • β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
  • γ (gamma) - although transcribed by the same gene, this PPAR through is expressed in three forms:
    • γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
    • γ2 - expressed mainly in adipose tissue
    • γ3 - expressed in macrophages, large intestine, white adipose tissue.

It does seem that activating alpha, gamma and delta has potential benefit.

The PPAR alpha agonist PEA is available as a supplement and as food for medical purposes In Italy and Spain.  It has been proposed for various inflammatory and pain syndromes. A large trial at a Skoda car factory in 1972 showed that PEA was protective against flu and the common cold.


Fibrate drugs are PPAR alpha agonist drugs used to lower cholesterol. A key point here is that these drugs also activate other types of PPAR as well.
PPAR gamma agonists are widely used to treat diabetes.  They improve insulin sensitivity and decrease some inflammatory responses. They lower cholesterol.
PPAR delta has various antidiabetic effects and agonism of PPAR delta changes the body's fuel preference from glucose to lipids. Recently it was shown that PPAR delta can be activated to promote biogenesis of mitochondria.
It does appear likely that there is some interaction between the PPARs.
Using the mild PPAR gamma agonist, Sytrinol, which gives a long term cholesterol lowering effect, gives a short term cognitive and behavioral improvement in autism.
Pioglitazone is used to lower glucose levels in type 2 diabetes and is a PPAR gamma agonist.  It has been shown to have a positive effect in autism and more trials are in progress. It also binds to a lesser extent to PPAR alpha.
Our reader Maja is investigating whether Sytrinol will maintain its initial good effect when combined with a mild PPAR alpha agonist, like PEA. 

Pan-agonists of PPAR

Bezafibrate appears to be the best known “pan-agonist” of PPAR alpha, gamma and delta.

The PPARpan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome 

   
Bezafibrate as treatment option in patients with mitochondrial complex I (CI) deficiency

These results support bezafibrate as a promising treatment option for specific subgroups of patients with CI deficiency.

Less well known is the natural substance Berberine. 




The multifaceted drug Telmisartan, from a recent post, is also a pan-agonist of PPARs. It is usually quoted as being a PPAR delta agonist. 




AICAR

The drug AICAR is thought of as an AMPK activator rather than a PPAR agonist, but it does affect all three types of PPAR.

Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.


Conclusion

It looks like some athletes, seeking an advantage, are already using the above strategies to improve their exercise endurance; having more mitochondria is of course a competitive advantage.  A list of all the substances banned in sport might be another good source of therapies not only for autism, but also dementia.
Since mitochondrial dysfunction is a feature of Parkinson’s, Huntington’s and Alzheimer’s there are some investigations ongoing. There is even a trial to perk up the mitochondria in people with Bipolar using Bezafibrate.
It is odd that Sytrinol has only a short term positive effect in most people with autism, although our reader RG’s daughter has a long term benefit. I suspect some people may need a pan-agonist, there may be some interaction/crosstalk/ feedback that we are not aware of.
It would be nice to have some data on the relative potency of Bezafibrate,  Telmisartan and Berberine across alpha, delta and gamma receptors, otherwise we are left with trial and error.
The advantage of Berberine is that it is an OTC supplement.
AICAR is also interesting.