Mitochondrial Dysfunction in Autism and Other Disorders, Can Diet Help?

Update May 8, 2014 as published in the journal Pediatrics May, 2014, study led by Cecilia Giulivi, PhD. confirms mitochondrial deficits in children with autism 19

Someone in our nonprofit group just asked “My Aunt sent me an article about research that found children with autism have mitochondrial problems. I know people in this group know so much so just curious if we are supposed to test for this? And if so what do you do for it?”

Great question!  The study probably shared was the one that was just published in the December 1, 2010 issue of the Journal of the American Medical Association; `Mitochondrial Dysfunction in Autism’ led by Cecilia Giulivi, PhD. 1  The study found that it was more common in children with autism to have mitochondrial dysfunction or deficits mitochondrial DNA (mtDNA) abnormalities, including overreplication and deletions in children with autism than in typically developing children.

According to Isaac Pessah, director of the Center for Children’s Environmental Health and Disease Prevention, a UC Davis MIND Institute researcher and professor of molecular biosciences at the UC Davis School of Veterinary Medicine “The various dysfunctions we measured are probably even more extreme in brain cells, which rely exclusively on mitochondria for energy” 2

While this study was completed with just 20 children, 10 of them with severe autism, there is much research that links mitochondrial dysfunction to several neurological conditions, including Parkinson’s disease, Alzheimer’s disease, schizophrenia, and bipolar disorder.

But perhaps you don’t even know what mitochondria is and what it does.  Mitochondria are known as the powerhouses of the cell.  Harvard University and XVIVO together developed the following beautiful 3D animation journey for Harvard’s undergraduate Molecular and Cellular Biology students about the microscopic world of mitochondria which may give all a better glimpse into the world of mitochondria. The following video is titled “Powering the Cell”

So what can be the cause/s of mitochondrial dysfunction?  There are numerous environmental factors.  One could be drug toxicity.

A report ‘Drug-Induced Mitochondrial Dysfunction: An Emerging Model for Idiosyncratic Drug Toxicity’ by James A. Dykens of Pfizer Drug Safety Research & Development 4 is a comprehensive look at numerous medications including some that may be used on children including certain antibiotics or antivirals that have black box warnings.

As this image shows clearly; mitochondria is a “complex organelle that can fail in many ways’

Numerous drugs have mitochondrial liabilities. The following are just a few key points:

• Many, but not all, drugs with organ toxicity have a mitochondrial liability.

– Screen of > 550 drugs reveals 34% have mitochondrial liabilities.

• Depending on potency, if a drug has a mitochondrial liability, it will have deleterious consequences.

• Severity of such adverse effects is idiosyncratic.

– Function of organ history and genetics (incl. mtDNA).

• Preclinical assessments are done in young, perfectly healthy animals.

– Threshold effects and physiological scope.

What is interesting about this is the amount of children with autism being treated with antiviral,  ADHD, or other medications. So of course my question is were the 10 autistic children from this study ever on any of the medications?

According to a paper published July 3, 2013 in Science Translational Medicine,certain antibiotics cause mammalian mitochondria to fail, which in turn leads to tissue damage. 18

“What the authors are suggesting is that in addition to the bactericidal properties of antibiotics, they also affect . . . the mitochondria,” said Navdeep Chandel, a professor of medicine and cellular biology at Northwestern University in Chicago, who was not involved in the work. “And what’s fascinating about that is that mitochondria are thought to be [ancient] bacteria themselves.” 18

While there are various factors that can affect the mitochondria including those you see in the image above; age, physical activity, genetics, underlying disease, etc. perhaps one of the most well known and easiest for us to control is through diet.

It has been said that Western medicine looks at each organ separately while Eastern medicine (ayurveda) looks at the whole body. In looking over the research which examined diet and it’s affect on mitochondria,  if poor diet and lifestyle can hurt the mitochondria as recent research is showing 5, 6, 7, 8, it is logical that mitochondria may also be helped by encouraging and raising awareness to the importance of healthier diet and lifestyle.

In a USDA article ‘Mitochondria: Mediators between diet and disease’ 5 written about diet-related mitochondrial dysfunction or as many in our nonprofit group call them “mito disorders”, the author explains the essential need for certain nutrients for mitochondrial health:

“Mitochondria take electrons extracted from the food we eat and push them through a series of steps that ends with the production of a compound called ATP. ATP provides the energy that drives the cellular processes needed for life. But in the process of producing energy, mitochondria also produce potentially harmful substances called reactive oxygen species or ROS. While the concentration of ROS in cells usually is well-controlled, diet can influence mitochondrial function in ways that increase the production of ROS to levels that become harmful to the mitochondria.In order to understand the relationship between diet, mitochondrial function and disease, it is important to understand how ROS can cause long-term, irreversible damage to mitochondria. Most of us know that cells have DNA that harbors the genes that determine our biological characteristics. Not as well- known is that mitochondria contain their own DNA whose genes determine the ability of mitochondria to use electrons — derived from food — to produce energy.ROS produced by the mitochondria can damage the mitochondrial DNA. This damage can cause genetic mutations that impair the ability of mitochondria to generate energy. Over time, the accumulation of these mutations can cause mitochondria to lose their ability to produce sufficient energy to meet cellular needs, and as a consequence, disease may follow. Mitochondrial dysfunction resulting from accumulated mutations in mitochondrial DNA has been implicated in heart failure, neurodegenerative diseases such as Alzheimer’s disease, diabetes and cancer. Mitochondrial dysfunction also can contribute to obesity by causing abnormal cellular use of carbohydrates and fats.Although the food we eat ultimately supplies the electrons that mitochondria use to produce energy, food also supplies other nutrients, particularly minerals such as iron, copper and zinc and certain vitamins, such as biotin, vitamin B6 and pantothenic acid, which support mitochondrial function. These minerals and vitamins are either components of the mechanism that mitochondria use to move electrons through the energy-producing steps or help synthesize the components in these steps.If dietary intake of these vitamins and minerals is inadequate, electrons derived from food cannot move efficiently through the energy-producing steps. Instead of contributing to energy production, the electrons then help increase the production of ROS, which in turn increases the rate of mutations in mitochondrial genes. It is at this level, the crossroad between mitochondrial energy production and ROS production, that diet can influence the development of disease.”

This same author also states the findings that in spite of the importance of certain nutrients for mitochondrial health, that “in the U.S., a significant percentage of people — from 10 percent to 25 percent — do not meet dietary requirements for iron, zinc or vitamin B6. Furthermore, among pregnant women, 10 percent do not meet the dietary requirement for copper, more than 75 percent do not meet the dietary requirement for iron, and near 40 percent do not meet the dietary requirement for biotin.”

TEDX How Food and Nutrition Help; Minding Your Mitochondria: Dr. Terry Wahls

And another important area being investigated “nutritional programming,” which occurs during gestation —where genes are turned on or off in response to various factors, including maternal diet and nutrition. Researchers are investigating whether the low intakes of iron (remember it’s more than 75% that do not meet the dietary requirement for iron according to the USDA article 5), copper or zinc during pregnancy can have long-term effects on mitochondrial function in offspring. Because such nutritional programming can affect susceptibility to health risks later in life, the researchers are studying whether such low intakes during pregnancy can promote disease as offspring age.”

In recent animal studies we have the answer, yes.  In an animal study presented at the American College of Neuropsychopharmacology’s 49th Annual Meeting the findings showed a high-fat diet in pregnancy was linked to inflammation in the offspring with irreversible negative brain changes that stretched into adulthood, affecting as well immune function and behavior.

“Obesity is well characterized as a systemic inflammatory condition, and is also associated with cognitive disruption, suggesting a link between the two. We assessed whether peripheral inflammation in maternal obesity may be transferred to the offspring brain, in particular, the hippocampus, and thereby result in cognitive dysfunction. Rat dams were fed a high-saturated-fat diet (SFD), a high-trans-fat diet (TFD), or a low-fat diet (LFD) for 4 wk prior to mating, and remained on the diet throughout pregnancy and lactation. SFD/TFD exposure significantly increased body weight in both dams and pups compared to controls. Microglial activation markers were increased in the hippocampus of SFD/TFD pups at birth. At weaning and in adulthood, proinflammatory cytokine expression was strikingly increased in the periphery and hippocampus following a bacterial challenge [lipopolysaccharide (LPS)] in the SFD/TFD groups compared to controls. Microglial activation within the hippocampus was also increased basally in SFD rats, suggesting a chronic priming of the cells. Finally, there were marked changes in anxiety and spatial learning in SFD/TFD groups. These effects were all observed in adulthood, even after the pups were placed on standard chow at weaning, suggesting these outcomes were programmed early in life” 6

“This is a first look at the effects of mothers’ obesity on the fetal brain,” said Staci Bilbo, PhD, lead author of the study and assistant professor of psychology and neuroscience at Duke University, Durham, North Carolina.

“Previous research has shown a link between obesity and inflammation in the body — outside of the brain — but little is known about whether obesity in a pregnant mother can affect the way the brain develops in her offspring.” 7

And it’s not just prenatal nutrients that are important. Research has also found that low serum zinc and copper levels and dietary habits associated with serum zinc and copper in 12- to 36-month-old children from low-income families put them at risk for iron deficiency 8 which based on research would be putting the health of their mitochondria at risk as well.6, 7, 9  At least one animal study shows the link between extended high fat, sugar diets will affect the mitochondria which can affect various areas of the body, including the muscles.

“We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity” 9

Feeding a child from a fast food restaurant like McDonald’s, Taco Bell, and Burger King is easier and cheaper than feeding a child foods that are healthier.  Statistically more low income parents turn to fast foods  high in fat and sugar to feed their children.  High fat and sugar diets are linked to metabolic and mitochondrial dysfunction. 6 7  Early December 2010, researchers at Yale University’s Rudd Center for Food Policy and Obesity, released an analysis which examined fast food marketing and nutrition trends and found fast food restaurants offer unhealthy sides and drinks 84 percent of the time, in lieu of their more nutritious offerings like apple slices, yogurt, and juice. 10

Here’s a great video that sums up the problem with how many are feeding our future; the children

Ongoing publications from UC Davis who is examining children through the Childhood Autism Risk From Genes and Environment (CHARGE) study in California who has discovered mitochondrial dysfunction lead to problems with energy. Interestingly, these abnormalities were not found in neurons on a brain biopsy but from examining white blood cells called lymphocytes. This means the energy deficit was a systemic problem — not one residing solely in the brain.  CHARGE, a population-based, case-control investigation with confirmed autism cases and age-matched, genetically unrelated, typically developing controls, that was launched in 2003 and is still ongoing. is the first comprehensive study of environmental causes and risk factors for autism and developmental delay.

Copper?

One of the nutrients that is needed for healthy mitochondria is copper. It’s a delicate balance of having just the right amount, not too much or too little. However it’s a nutrient that appears to be deficient more often than thought in both plants and humans today. As one USDA article states, there is neglect regarding copper dietary intake. 11 Copper deficiency is associated with severe neurological disorder. “Copper deficiency has been described as resulting in severe neurological impairment. However, mechanisms underlying a copper deficiency are presently unknown.” 12

And if we are talking about autism, celiac appears to be common in the autism world, and just on the rise in general. As a NIH consensus development conference on celiac disease found “Celiac disease is widely considered to be a rare disease in the United States. However, recent studies, primarily in Europe but also in the United States, suggest that its prevalence is much higher than previous estimates, raising the concern that the disease is widely under-recognized” 13 And how does once again copper tie in to this? From a 2009 Journal of Clinical Gastroenterology “Copper deficiency is an uncommonly reported complication of celiac disease that has not received much attention in recent years.” 14

Researchers at the Montreal Neurological Institute at McGill University are studying how copper is processed in our bodies and its distinct role in early development, particularly how it affects the mitochondria 15 From a USDA article I read;

“It is easy to find a diet that fails to meet (copper) dietary references intakes. For instance, a tuna fish salad made with lettuce, mayonnaise and salad oil is very low in copper. The recipe can be improved by adding high-copper foods such as soy or other legumes, mushrooms and sunflower or other seeds. Other good sources of copper include some ready-to-eat cereals, chocolate, nuts, peanut butter, liver and oysters.The panel also defined the tolerable upper intake for adults as 10 mg daily and suggested that it is quite unlikely that people will reach even half this level even if dietary supplements of copper and small amounts of copper in drinking water are included.I hope that neglect of copper will fade with the new recommendations. In any event, many of us probably will benefit from eating foods high in copper more frequently.” 11

And it may not just be diet in the case of low levels of copper. I found research, one titled “Copper deficiency in world crops” that the use of nitrogen fertilizer depleted copper in various vegetations, as well as zinc, iron, manganese and boron, nutrients important for reducing oxidative stress to the mitochondria. 16 17

I probably should sum up as of course this is a subject that can go on, so let me end on another theory on perhaps why a natural functional food like Nutriiveda (NV original) is helping so dramatically.  NV Original is is an all natural GFCF functional food, that like fish oils, has been successful nutritional strategy for many with various special needs like autism. All ingredients in NV original are certified foods that provide to the body a rich profile of all the essential amino acids over 22 vitamins and minerals, high quality proteins, and soluble fiber.

Perhaps just as it’s best not to look at each organ separately,and to look at the whole body; we should try to look at food the same way -as a whole.  In that light it makes sense that  food that provides essential nutrients can benefit the whole body.

References;

1. Mitochondrial Dysfunction in Autism
   JAMA. December 8, 2010, Vol 304, No. 22, pp 2441-2548
   Cecilia Giulivi, PhD; Yi-Fan Zhang, BS; Alicja Omanska-Klusek, MS; Catherine Ross-Inta, BS; Sarah Wong, BS; Irva Hertz-Picciotto, PhD; Flora Tassone, PhD; 8. Isaac N. Pessah, PhD
2. UC Davis study finds children with autism have mitochondrial dysfunction
   University of California – Davis Health System
3. Powering the Cell 3D Animation
4. Drug-Induced Mitochondrial Toxicity: A New Model of Idiosyncratic Adverse Drug Responses
   James A. Dykens
   Pfizer Drug Safety Research & Development, Sandwich, England
5. Mitochondria: Mediators between diet and disease
   Tom Johnson
   United States Department of Agriculture Agricultural Research Service
6. Enduring consequences of maternal obesity for brain inflammation and behavior of offspring.
   FASEB J. 2010 Jun;24(6):2104-15. Epub 2010 Feb 2.
   Bilbo SD, Tsang V.
   Duke University, Department of Psychology and Neuroscience, Durham, NC 27708, USA. [email protected]
7. High-Fat Diet in Pregnancy Linked to Brain Inflammation in Offspring, Animal Study Suggests
   Irreversible Effects Stretch Into Adulthood, Affecting Immune Function and Behavior
8. The prevalence of low serum zinc and copper levels and dietary habits associated with serum zinc and copper in 12- to 36-month-old children from low-income families at risk for iron deficiency.
   J Am Diet Assoc. 2007 Nov;107(11):1924-9.
   Schneider JM, Fujii ML, Lamp CL, Lönnerdal B, Zidenberg-Cherr S.
   Department of Nutrition, University of California, Davis, California, USA.
9. Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice
   Charlotte Bonnard, Annie Durand,Simone Peyrol, Emilie Chanseaume, Marie-Agnes Chauvin, Béatrice Morio, Hubert Vidal, Jennifer Rieusset
   J Clin Invest. 2008 February 1; 118(2): 789–800.
   American Society for Clinical Investigation
10. Just released analysis from Yale University’s Rudd Center for Food Policy and Obesity
11. Copper Gets New Status
    Leslie M. Klevay
    United States Department of Agriculture Agricultural Research Service
12. Copper deficiency associated with severe neurological disorder — A genetic work-up of possible mutations in copper transport proteins
    Journal of the Neurological Sciences
    Volume 291, Issue 1 , Pages 95-97, 15 April 2010
    Carmen Noelker, Thomas Klockgether, Michael Bacher,
    Department of Neurology, Philipps-University Marburg, Rudolf-Bultmann-Straße 8, 35039 Marburg, Germany
13. NIH Consensus Development Conference on Celiac Disease
    June 28−30, 2004
14. Copper Deficiency in Celiac Disease
    Journal of Clinical Gastroenterology:
    February 2009 – Volume 43 – Issue 2 – pp 162-164
    Halfdanarson, Thorvardur R. MD*; Kumar, Neeraj MD†; Hogan, William J. MBBCh*; Murray, Joseph A. MD‡
15. Mitochondria Has A Role In Cellular Copper Regulation
    ScienceDaily (May 2, 2007)
16. Copper deficiency in world crops
    Alloway B.J., Tills A.R. (1984):Outlook Agric., 13: 32–42.
    The effect of rate of application of nitrogen fertilizer on soil copper uptake by barley under unirrigated conditions
    R. C. Tiwaria1 and J. Adinarayanaa1
    a1 Department of Soil Science and Agricultural Chemistry, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi-221005, India
17. Micronutrients in the Avocado
    Effects of nitrogen fertilization on the zinc, copper, iron,
    manganese and boron content of Fuerte avocado leaves
    California Agriculture. 1958. 12(10):11.
    C. K. Labanauskas, T. W. Embleton, W. W. Jones
18. Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells Sci Transl Med 3 July 2013: Vol. 5, Issue 192, p. 192ra85 Sci. Transl. Med.
19. Study confirms mitochondrial deficits in children with autism UC Davis Health System PEDIATRICS Vol. 133 No. 5 May 1, 2014 Deficits in Bioenergetics and Impaired Immune Response in Granulocytes From Children With Autism Eleonora Napoli, PhDa, Sarah Wong, BSa, Irva Hertz-Picciotto, MD, PhDb,c, and Cecilia Giulivi, PhDa,c

=====
Written by Lisa Geng, mother to two boys that were both “late talkers” who are doing great today. President and Founder of the Cherab Foundation, and Co Author of The Late Talker book St Martin’s Press