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.


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


  1. Are there supplements that have qualities similar to DMF? Would cinnamon? thank you, CA

  2. CA, cinnamon,niacin and the ketone BHB all affect HCAR2 in the same way as DMF. Sulforaphane seems to have the same effect on NFR2 as DMF.

    I have found cinnamon, broccoli sprouts and BHB to have a positive effect, but I think DMF even at a tiny dose is much more potent. DMF can also be given at a standardized consistent dose, which is not the case with most supplements.

    I came across DMF by trying to figure out why the ketone BHB is beneficial in some autism.

    1. So, is it worth adding Dimethyl fumarate to Betahydroxybutyrate?


    2. It is definitely worth trying DMF even if you already use BHB.

  3. Hello Peter and friends,

    Hope everyone is well! With the release of the SfN 2019 abstracts (which I know Ling has already read ;-) ), we've had a lot of interesting new info, and again, the following two papers add more interesting info to this puzzle:

    I first learned about KCC2 by learning about NKCC1 via Peter's information about Bumetanide, and that had led me to the following paper:

    This one is really interesting, especially when you read the full text version.

    All this leads to me ask the following: I haven't trialed anything new in a while, and was holding off but KCC2 (increasing it) appears to be a very interesting target (especially when you are Bumetanideless) and Resveratrol and Piperine are two natural compounds that do this via different mechanism of action.

    Of course, my concern with Piperine is that it's primary use is in increasing absorption of other nutrients, which is actually something I want to avoid with respect to the other supplements I use. So I've been trying to find out how long after using Piperine this effect is greatly reduced. That is, how long after Piperine can one assume that it is no longer enhancing absorption. Has anyone ever looked into this and know this off-hand? I keep finding a study about B vitamins after co-administration, 2 and 4 hours, but can't find how long its effect lasts (or is greatly diminished).

    I'm thinking about using Piperine on its own with enough time between it and other supplements that it doesn't enhance anything else.

    Thanks in advance to anyone who has this info!


    1. Interesting quote from your link no 2 above AJ on phenotypes:

      "The authors convincingly showed that the homozygous S940A knockin mice with increased neuronal [Cl−]i [=reduced inhibitory strength of GABA] during P10 to P19 period have significantly reduced preference for social interaction, whereas homozygous T906A/T1007A mice with decreased neuronal [Cl−]i showed increased sociability compared to wild-type mice. These results are in perfect agreement with our finding showing that partial inactivation of KCC2 promotes reduction of sociability."

      I wonder how this correlates to Down's syndrome, where kids seem to be very social?


    2. Hi Ling!

      That is a fascinating question, because you are exactly right, DS kids are more social than their NT counterparts.

      I've found lately that I'm seeing a lot more attention being brought to KCC2, and since it's the other side of the chloride homeostasis mechanism (I.e. NKCC1 pumps it in, KCC2 pumps it out), I've wondered if I'm better off trialing a KCC2 agonist versus a NKCC1 anatagonist, and mechanistically, there may even be some benefits in doing so (above and beyond the fact that antagonizing NKCC1 has some other issues like diuresis because of its presence in the kidneys).

      The fact that such a relatively high % of kids seem to improve on Bumetanide tells me that many of affected pathways of ASD must in some way converge on chloride homeostasis, so boosting KCC2 activity for a period of time (e.g. 2 months) would be a good test to see if one's child is affected by chloride homeostasis issues

      The older paper I had referenced showed Resveratrol and Piperine did this via different mechanisms of action on KCC2, so that's why I wanted to use them concurrently. I believe that Piperine was injected, but it still may be beneficial orally just in case it still hits its target. Even if the effect is small, maybe combined with Resveratrol, it may have some noticeable effect.

      By the way, I saw your list of SfN papers - great list! I'll post a few of my favorites soon too.


    3. E/I balance in Rett's syndrome was also a good read. Your paper AJ lead me directly to this one stating that:

      "Loss of MeCP2 leads to reduced expression of the Cl− exporter KCC2 and reduction of the KCC2/NKCC1 ratio, with altered GABA reversal potential in pyramidal neurons. Treatment with the NKCC1 inhibitor bumetanide restores the reversal potential."


      "Deletion of MeCP2 from PV+ neurons alone recapitulates effects of global MeCP2 deletion on pyramidal neurons."


      "Treatment of mutant mice with rhIGF1 restores PV+ and pyramidal neuron responses, as well as KCC2 expression. These results demonstrate that reduction of both inhibition and excitation [..] contributes to the cortical circuit deficits of RTT, and their joint restoration may be crucial for functionally correcting these deficits."


  4. The GABA switch happens in Shank3, instead increased glutamatergic activity seems to cause ASD in this mice model:

    "our team has discovered major alterations of the GABA developmental sequence in two rodent models of autism, the Fragile X and in utero valproic acid models that, respectively, mimic a genetic mutation and environmental insult linked to ASD
    we evaluated Shank3-mutant mice, a frequently investigated genetic mouse model of ASD
    We report that in CA3 pyramidal neurons, the driving force and inhibitory action of GABA are not different in naïve and Shank3-mutant age-matched animals at birth and during the second postnatal week. In contrast, the frequency of spontaneous excitatory postsynaptic currents is already enhanced at birth and persists through postnatal day 15. Therefore, in CA3 pyramidal neurons of Shank3-mutant mice, glutamatergic but not GABAergic activity is affected at early developmental stages, hence reflecting the heterogeneity of mechanisms underlying the pathogenesis of ASD.
    averting the hypothesis that bumetanide will work as a potential treatment"

    I got the impression that they meant that prenatal Bumetanide won't prevent ASD causing events to happen here.


  5. As I'm at it I'll throw in an abstract on Bumetanide and fetal alcohol spectrum disorders (FASD) too:

    "In a model of FASD, maternal bumetanide treatment prevented interneuronopathy in the prefrontal cortex of ethanol exposed offspring, including deficits in behavioral flexibility. These findings position interneuronopathy as a mechanism of FASD symptomatology, and posit NKCC1 as a pharmacological target for the management of FASD."


  6. E/I balance in autism has been proposed since 2003. 15 years later the concept is studied and modulated in mice models, and in a few cases resulting in treatments for humans. But is the simple E/I model a sufficient final answer? Certainly not, as readers of this blog already know.
    It is refreshing to see that there are others out there who already are picturing the next steps for E/I balance research in neuropathologies:

    Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders

    "we would propose that the next phase of research should focus on
    (1) classifying the many possible “E-I imbalances” into some tractable categories of circuit derangements,
    (2) identifying biomarkers that might indicate which type of circuit derangement is present in a particular individual, and
    (3) testing whether determining what type of E-I imbalance/ circuit derangement is present in a given individual is sufficient to predict what sorts of behavioral abnormalities might be present, and/or which therapies might be effective.
    Even though there may be many conditions involving deficient inhibition, for which behavior can be normalized by non-specifically increasing inhibition, in other cases, excessive or altered inhibition might be at fault, or it may be necessary to specifically enhance inhibition from particular sources (PV interneurons) or onto defined targets (e.g., D2R+ mPFC neurons). These scenarios represent fundamentally different kinds of circuit derangements that will likely require different types of therapeutic interventions. We argue that it is critical to understand what sort of circuit derangement is present"


  7. What do you think about CBD oil?

    1. Denisa, CBD and cannabinoids more generally do have properties that may improve some autism and some epilepsy.

      The original Charlotte's web product was developed to treat Charlotte, who has Dravet Sydrome (severe epilepsy + autism). To keep it legal they have changed the ingredients. One reader a few years ago found the old Charlotte's web effective, but not the newer one.

      A big problem with CBD products is that they rarely contain what they say on the label.

      Another cannabinoid, CBDV, is now being tested in an clinical trial for autism.

      You would have to make your own trial to see if a particular brand of CBD oil is beneficial in your specific case.

  8. I want to learn more about NRF-1.
    It seems to link to not only NRF2, but also to estrogenic activity, NMDA receptors, mitochondrial activity and neurite outgrowth and much more.

    The first article here has a title that might put you down, but some parts of it does look interesting:

    "dysregulation of NRF1 and its targets may be involved in the pathogenesis of neurodegenerative diseases
    NRF1 is an emerging potential target for therapeutic intervention for brain diseases, including AD
    estrogen effects on brain cells may be in part mediated through ROS signaling biomolecules that regulate estrogen-induced NRF-1 activation. This, in turn, may control the expression of NRF-1-regulatable genes
    NRF1 regulates neurite outgrowth. NRF1 regulates important subunits of NMDA receptors—NR1 and NR2b (Grin1 and Grin2b) and AMPA receptor subunit 2 (GluR2).
    NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence"

    And for anyone with interest in NMDArs maybe add some reading from this one:
    NRF-2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: Both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission

    "NRF-2 functionally regulates critical Grin1 and Grin2b subunits of NMDA receptors
    Silencing NRF-2 prevented KCl-induced up-regulation of Grin1, Grin2b, and COX
    NRF-2 (GABP) transcriptionally coregulates energy metabolism and neuronal activity
    NRF-2 and NRF-1 regulate NMDA receptors and COX in a concurrent and parallel manner"

    So, it looks like anyone benefitting from NRF-2 upregulators might be interested to try something that enhances NRF-1 too(?)



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