News release on mitochondrial disorders mentions glutathione

Discussion in 'Fibromyalgia Main Forum' started by banya, Feb 10, 2009.

  1. banya

    banya New Member

    STANFORD, Calif. —Scientists at Stanford University School of Medicine have devised a much-needed way to monitor and find treatments for a mysterious and devastating group of metabolic diseases that arise from mutations in cells' fuel-burning mechanism.

    Mitochondrial disorders can cause organ failure, seizures, stroke-like episodes and premature death. The diseases—more than three dozen in total—arise from genetic errors of the mitochondria, the cell structures that process oxygen and turn food molecules into useable energy. Mitochondrial disorders affect one in 4,000 kids and one in 8,500 adults. They are difficult to diagnose, and no treatments or cures exist.

    But that could soon change. A team at Stanford and Lucile Packard Children's Hospital has discovered a biological marker they can use to monitor the diseases. The finding will enable researchers to hunt for treatments and help physicians check patients' status before health crises erupt. The research was published online Feb. 9 in the Proceedings of the National Academy of Sciences.

    "When a car engine doesn't work right, it smokes," said senior study author Greg Enns, MB, ChB, who is professor of pediatrics at Stanford University School of Medicine and director of the biochemical genetics program at Packard. "What we looked for is, in essence, biochemical smoke."

    Like a car engine, when mitochondria are not burning fuel cleanly, they kick out nasty gunk. Defective mitochondria produce large quantities of oxygen free radicals—highly reactive molecules that damage DNA and cell structures. Comparing patients who have a mitochondrial disorder with healthy people in the control group, Enns' team searched for signs that free radicals overtax patients' natural antioxidant defense systems. And they found it.

    "Even when these patients are coming into the clinic looking pretty healthy, they have evidence of extra metabolic stress," Enns said, noting the findings were surprising because none of the patients were in the midst of a health crisis such as organ failure when blood samples were taken. It is the first time such signs have been uniformly shown in the blood of patients across a wide range of mitochondrial disorders, he added.

    The team saw that levels of glutathione, the body's primary antioxidant, were significantly reduced in white blood cells from the 20 mitochondrial disease patients in the study. The observation means patients' antioxidant defenses were indeed depleted. Glutathione was also diminished in nine patients with organic acidemias, another group of metabolic diseases that researchers think may be associated with aberrant mitochondrial function.

    A second finding gave the researchers a big hint about where to hunt for treatments. Patients taking antioxidant supplements did not have depleted glutathione, they found. Scientists have long suspected antioxidants such as vitamin C and vitamin E might help patients with mitochondrial disease or organic acidemias, and doctors sometimes suggest the supplements to their patients. But no one has been able to test whether they work.

    "As a clinician, one of the most frustrating things has been not being sure if supplements are doing any good," said Enns. "Now we're able to take a baseline blood reading and see `before' and `after' snapshots."

    William Craigen, MD, PhD, the director of the metabolic clinic at Texas Children's Hospital, called this finding "the beginning of insight into the mechanisms of mitochondrial disease." Craigen, who is also medical director for the mitochondrial diagnostic lab at Baylor College of Medicine, was not involved in the Stanford study. "This new research provides an opportunity to start treating a heterogeneous group of diseases in a single fashion, with a simple and easy-to-administer treatment, potentially improving patients' long-term outcomes," he added.

    Glutathione measurements could also help diagnose patients, Enns said, by giving physicians a clear indication that something is awry in the mitochondria. Genetic and molecular tests have already led to increases in the number of diagnoses, but the diagnosis is still difficult to pin down.

    The method Enns' team used to measure glutathione, called high-dimensional flow cytometry, has limitations: it requires very fresh blood samples, uses expensive equipment only available in research labs, and provides relative rather than absolute glutathione measurements. Now that the team knows what metabolic change to look for, they're working to develop a more broadly applicable measurement technique.

    And glutathione measurements could help scientists unravel other disease mysteries, too. "You name the disease, you can postulate mitochondrial involvement," Enns said. "It's been proposed for everything from poor vision to hearing loss, kidney disease, liver disease, autism spectrum disorders, diabetes, Alzheimer disease, cancers. Our work could lead to research on therapies for a broad range of disorders."

    Enns collaborated with research associate Kondala Atkuri, PhD; associate professor of pathology Tina Cowan, PhD; professor emeritus of genetics Leonard Herzenberg, PhD; and research professor of genetics Leonore Herzenberg, PhD, who is also a member of the Stanford Cancer Center. The Herzenbergs have a financial interest in BioAdvantex, a company whose dietary supplement, PharmaNAC, is intended to increase glutathione levels. The study was funded by grants from the United Mitochondrial Disease Foundation, the Lucile Packard Children's Hospital Pediatric Health Research Fund and the Arline and Pete Harman Scholarship.
  2. richvank

    richvank New Member

    Hi banya.

    Thanks for posting this. I'm very happy to see that the connection between glutathione depletion and mitochondrial dysfunction is getting some attention in the mito disease community.

    As you may know, the Glutathione Depletion--Methylation Cycle Block hypothesis for CFS postulates that glutathione depletion is the initial cause of the mito dysfunction in CFS. Mito dysfunction in CFS was also the subject of the recent paper by Myhill et al., and it has also been getting a lot of attention in autism lately, which shares much of the same biochemical issues with CFS.

    I don't have a copy of the full paper from Stanford yet, but I note that they found glutathione depletion in people who had abnormalities in their urine amino acids tests, also. Urine amino acids abnormalities are also found in CFS, such as on the Genovations Metabolic Analysis Profile, and some of them are indicative of mito dysfunction.

    These researchers may not be aware of the Vitamin Diagnostics, Inc. tests for blood plasma reduced and oxidized glutathione, which are already commercially available.

    I think the line between mito disease and mito dysfunction may be a little blurry. If glutathione testing becomes more common among the mito disease specialists, I think they will start to pick up cases of CFS, and maybe they will get more interested in it. All in all, I think this is a very positive development. It's nice to see some of these things coming together!


    [This Message was Edited on 02/11/2009]
  3. SpecialK82

    SpecialK82 New Member

    Thanks so much for posting banya! I'm excited to hear of any research done in this area.

    Rich, as I understand, glutathione gets depleted when the mito is not working correctly, and then the glutathione depletion causes secondary problems - ie. free radicals running around - correct?

    But then you are saying that the glutathione depletion is the intial cause of the mito dysfunction in CFS - so I'm not clear - it's kind of like the chicken or the egg - which comes first??

    I thought by increasing the glutathione many of the secondary problems could be stopped but could it actually correct the mito dysfunction which would in turn stop the glutathione depletion?

    I apologize in advance as I know I need to go back and read all of your posts - thank you for all of your research in this area!

  4. richvank

    richvank New Member

    Hi, Kristina.

    The situation may be different in the genetic mito diseases from the way it is in CFS. You're right, there is a chicken and egg (or cart and horse) issue here. It takes ATP to make glutathione, and ATP is made by the mitochondria. So if some other problem (such as a genetic mutation in one of the genes that codes for a mito protein) torpedoes the ability of the mitos to make ATP, glutathione will become depleted. That is likely the situation in the genetic mito diseases.

    In CFS, on the other hand, according to my hypothesis, glutathione becomes depleted first, by some combination of a variety of stressors, and when glutathione goes down, the oxidizing free radicals rise, and superoxide in particular, shuts down aconitase in the Krebs cycle (which is located in the mitochondria), lowering the production of ATP. So in CFS, I believe that the glutathione depletion comes first. When the glutathione is restored, by lifting the block in the methylation cycle, which is what is holding it down, then the mitochondria should eventually work better again. I say eventually, because after glutathione goes down, toxins are allowed to accumulate in the mitochondria, and they have to be cleared out, which takes time.

    I might add that the other CFS researchers who are interested in the mito aspect do not agree with me completely, or they suggest variations in the initial steps of the process. Professor Marty Pall thinks that CFS starts with a problem in the nitric oxide and peroxynitrite, and that the rise in peroxynitrite is what shuts down the mitochondria. Dr. Paul Cheney thinks that something (maybe a virus) knocks down the antioxidant enzymes (glutathione peroxidase, superoxide dismutase and catalase), and that there is a problem with the recycling of glutathione, and that this leads to the mito dysfunction.

    People who have been on the methylation cycle block treatment for at least several months are reporting that they have more energy, while at the same time we have lab data on them that show that their glutathione levels have risen, and I interpret that combination to suggest that the mitochondria are working better because glutathione has been brought back up, which would be consistent with the hypothesis I've proposed. We are planning to report this next month at the IACFS/ME conference.

    Best regards,

    [This Message was Edited on 02/11/2009]
  5. grannyc

    grannyc New Member

    Or N Acetyl Cysteine is something I take every day to build my immune system. I take it along with the Antibiotic Protocal. I will say that after I started taking it I have noticed I don't catch everything so much. It also is good for the liver and your lungs. But if you do start taking it, do it slowly since it can cause some die off or Herx reaction. It also works a bit like a cillan.
  6. richvank

    richvank New Member

    Hi, grannyc.

    I'm glad to hear that NAC has been helping you. I do want to encourage caution with this supplement in CFS, though. NAC has been shown in rat experiments by Aposhian et al. to be able to move mercury into the brain. Many PWCs have elevated mercury levels because their glutathione levels have been low for a long time, and they have had continuous exposure to mercury evaporating from amalgam fillings in their teeth. The result of this combination is that inorganic mercuric ions build up in their bodies, because glutathione is what normally binds mercury so that it can be excreted. Mercury is a neurotoxin if it enters the brain, and one way it can get there is to be transported across the blood-brain barrier by NAC. Dr. David Quig of Doctor's Data Lab, who has specialized in heavy metal toxicity for many years, has recommended that the dosage be limited to 300 mg per day if significant amounts of heavy metals are believed to be present in the body.

    Dr. Cheney has noted that he is aware of two suicides of CFS patients that were associated with high intakes of NAC. While there is no proof of this, I suspect that mercury-induced neurotoxicity might have been involved.

    In my view, lifting the associated methylation cycle block is a better approach to raising glutathione in CFS. We have good lab data now that shows this works, and we are planning to present it at the IACFS/ME conference in Reno next month.

  7. banya

    banya New Member

    Rich, I have to agree with you that the line between having a mito disease and a mito dysfunction may be a little blurry. Actually, more likely VERY blurred. Just a couple of weeks ago I attended a talk given by Dr. Cohen (mito specialist) at the Cleveland Clinic. The discussion was on this very topic. My impression was that in the mito "disease" world, they seem to regard most of these problems as having a genetic basis, but in many cases there may be a low mutation load which may result in a patient having milder health issues - or a delayed (adult) onset of medical problems. As I'm sure you know, aging itself is caused by the loss of mitochondria and if you are mito challenged - you'll eventually reach a threshold where you're going to start having medical problems.

    But the topic of how other things can damage your mitochondria was also discussed and the researchers seem to be more aware of the studies which are going on regarding toxins and viruses, etc and their role in damaging our cells. Much of the discussion centered around the topic of autism and how children with autism who have other medical problems along with this diagnosis, may very likely be suffering from a mitochondrial disease. Mitochondrial disease can cause autism like behavior.

    Anway, I did have a question for you regarding testing glutathione levels. Based on the Stanford study I'm wondering it is worth testing our levels if we are currently supplementing with high amounts of antioxidants. It sounds like our test results should be altered (showing improvement) by taking the antioxidants. Have you seen or noticed those same results? I suppose I wondered if there was a benefit to taking this test either before using the antioxidants or to stop taking them for a while -- to find out if a deficiency if even an issue. Please let me know your thoughts on this.

  8. richvank

    richvank New Member

    Hi, banya.

    Thanks for the information about Dr. Cohen's talk. It really is sounding like the mito disease community is getting interested in the causes of mito dysfunction, be they genomic polymorphisms, toxins or viruses. I think that's great!

    Dr. Myhill and I have written a draft of a paper that reviews the published evidence for mito dysfunction in CFS. We've made a couple of attempts to get it published, without success, but plan to try again. Maybe the climate is changing.

    I don't have much lab evidence about the ability of antioxidant supplementation to raise glutathione, but I have seen one or two methylation pathways panels (which include plasma glutathione) that have shown normal glutathione levels while the methylation cycle clearly still had a partial block. In one recent case, the person had been taking liposomal glutathione. So I suspect that doing that, at least, can boost the glutathione level, so long as one continues to do it. I don't know what the effect of other antioxidants would be on the glutathione level, but some of them should raise it, particularly those that don't rely on glutathione to recycle themselves. Vitamin C should work if taken in large dosage, such as near bowel tolerance levels, but smaller amounts may deplete glutathione further, because at small amounts oxidized vitamin C is reduced by glutathione. At large dosages, according to the late Dr. Robert Cathcart, the reaction equilibria are switched, and vitamin C will reduce oxidized glutathione.

    I do think there is value in measuring the glutathione level, whether it is done while still taking antioxidants or after stopping for a while. These two would give different information. Of course, as a researcher, I'd love to see both! If you are thinking of doing just one measurement, I would suggest stopping the antioxidants so that you will get a clear picture of what is going on, and I would also suggest doing the full methylation pathways panel from Vitamin Diagnostics, Inc., in Cliffwood, NJ.

    It's important to measure the plasma reduced glutathione, as is done by Vitamin Diagnostics. The other labs I'm aware of in the U.S. don't do what's necessary to measure reduced glutathione (you have to use special preservatives to keep the reduced glutathione from oxidizing during shipping and storage of samples), but just measure total glutathione. Also, most labs measure whole blood or red blood cell glutathione, which does not correspond well to the level of glutathione in tissue cells, since red blood cells are normally producers and net exporters of glutathione, as is the liver. The RBCs may still have a good total glutathione status while the tissue cells are depleted in reduced glutathione.

    Best regards,


  9. SpecialK82

    SpecialK82 New Member


    Thanks so much for taking the time to reply to me. I am very encouraged by your research results and I would like to start this protocal as soon as I can find a doctor that will support me.

    I am looking forward to your report at the IACFS/ME conference - thank you for keeping hope alive for us!


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