Posts Tagged ‘mitochondria’

What is mitochondria disease? What does it have to do with autism, and are there treatments?

November 18, 2011 22 comments

This week’s “Got Questions?” answer comes from Deepa Menon, MD, assistant medical director of the Center for Autism and Related Disorders, at Baltimore’s Kennedy Krieger Institute—an Autism Speaks Autism Treatment Network (ATN) site. Her research interests include metabolic and mitochondrial disorders and their association with autism.

Mitochondria are cell structures, or “organelles,” whose primary function is to supply a cell with energy. In essence, they turn sugar and fatty acids from food into the energy-carrying molecule adenosine triphosphate (ATP).

Virtually every cell in the body depends on ATP and mitochondria for energy. As a result, mitochondrial disorders can produce a wide variety of symptoms. The most common involve body systems that use a lot of energy. Muscles are a classic example, and mitochondrial dysfunction often produces muscle weakness and fatigue. When mitochondrial dysfunction affects the gastrointestinal system, symptoms can include constipation or diarrhea. When it affects the immune system, it can lead to frequent infections. Mitochondrial disorders can likewise cause failure to grow, kidney dysfunction and a many other medical problems.

The brain is another energy-demanding system. Here, mitochondrial dysfunction can produce such symptoms as developmental delay, hearing problems and seizures.

Over the last decade, there has been great interest in the possibility that mitochondrial disorders may underlie some of the symptoms of autism spectrum disorder (ASD). Currently we believe that around 5 to 10 percent of children with autism have mitochondrial dysfunction as the underlying cause of their symptoms.

Research suggests that many children diagnosed with autism and underlying mitochondrial dysfunction experienced regression following a simple childhood illness (ear infection, common cold, etc.) or other cause of fever or inflammation. Regression refers to a loss of developmental skills such as language or motor abilities. It may be accompanied by other symptoms of mitochondrial disorder such as fatigue, gastrointestinal distress, seizures and/or motor delays.

Laboratory testing of blood samples and urine show that many of these children (with ASD and mitochondrial dysfunction) have abnormally high  levels of certain amino acids and cellular waste products. This suggests that their cells are generating energy inefficiently with an excess of damaging byproducts.

When a child is diagnosed with ASD and mitochondrial dysfunction, treatment goals include a bolstering mitochondrial activity and protecting the mitochondria from further damage. Parents and affected individuals may be counseled to avoid (as much as possible) situations that stress mitochondria. Examples of these stresses include going for long periods between meals (prolonged fasting), infections that produce fevers, inflammation associated with dietary sensitivities and certain medications such as the antipsychotic haloperidol (Haldol), which is known to impair mitochondrial function.

Supportive treatment can include a prescription nutrient mixture containing the protein L-carnitine and the B-vitamin pantothenate, which is thought to bolster mitochondrial activity. This prescription mixture usually contains additional nutrients such as thiamine, nicotinamide, lipoic acid, and vitamins C and E. Coenzyme Q10 may be added for those who show low levels of CoQ10 on testing.

[Editor’s note: Autism Speaks continues to support research into the association of mitochondrial disease and autism and their effective treatments. For more information on these and other funded studies, please explore our Grant Search portal, here.]

Have a question? Email us at For more news and perspective, please visit the Autism Speaks science page.

New Trailblazer Awards fund innovative autism research

December 16, 2010 2 comments

Science advances in fits and starts. Part of Autism Speaks’ role as an advocacy and science funding organization is to find ways to identify and advance the science that could lead to improvements in the lives of those struggling with Autism Spectrum Disorders. New ideas bubble up frequently, however few mechanisms exist to support the exploration of unique and novel ideas.  The burden of evidence required to secure funding for a great idea is very high and often dissuades researchers from pushing for greater innovation and out-of-the-box thinking, resulting in research that is “safe” and moving at a pace that is slower than any of us would like.

To address this need, Autism Speaks has launched the Suzanne and Bob Wright Trailblazer Awards.  The Trailblazer Awards commemorate Autism Speaks’ fifth anniversary and honors our organization’s pioneering founders, Suzanne and Bob Wright.  We are grateful to the generous donors who have made contributions to support this special research innovation fund.

Trailblazer Awards provide seed funding to test out a novel idea or approach that has the potential to transform some aspect of autism research.  Importantly, applications for these awards are accepted and reviewed on a rolling basis so new ideas are evaluated quickly and those ripe for this mechanism meet with funding quickly.  The three funded projects summarized below will receive up to $100,000 for one year and each addresses a point of need as outlined in Autism Speaks’ Strategic Plan.

Mitochondria have been the focus of considerable buzz in autism research recently.  However, the reports on mitochondria’s control of cellular energy processes only scratch the surface of the complex web of cellular activities that these organelles orchestrate [see also mitochondrial and fever story]. Robert Naviaux, MD., Ph.D., (UCSD)  and his colleagues are grateful for the opportunity to pursue research on how mitochondrial metabolites may play a role in brain inflammation. “The Trailblazer award gives our lab the support to bring together 3 world-class groups to study the role of mitochondria in autism.  If successful, our results will provide the foundation for both fresh new therapies, but also for additional studies that clarify the role of mitochondria and the environment in the cause of autism,” said Naviaux.

The idea Dr. Naviaux brought to Autism Speaks focuses on a product of the mitochondria, called ATP, that is required for the development of brain cells and their communication with each other.  For cells to function properly, very specific quantities of ATP are required around the brain cells.   Naviaux will explore whether mitochondrial dysfunction, which can result in high concentrations of ATP in the space between cells, stimulates inflammation in the brain, and also alters connectivity between neurons.  Importantly, Dr. Naviaux and his colleagues will also test a compound that works against the effects of high concentrations of ATP as a potential therapy.  The effects of manipulating ATP and the pathways it tickles will be tested in a well-established mouse model for autism so the effects at both the cellular as well as behavior level can be compared before and after treatment. Read the grant abstract.

Phil Schwartz, Ph.D. (Children’s Hospital of Orange County) is building a unique resource that aims to bring personalized medical solutions to individuals living with autism.  The technology now exists to take a small sample of skin tissue and from that create stem cells that can be used to make personalized copies of any type of cell in the body.  Of interest to autism, of course, are brain cells. Schwartz and his colleagues have not only created neurons from skin cells, but they are also pioneering a method to incorporate them into living mouse brains so they can evaluate how these human-derived cells function as part of a circuit.  Dr. Schwartz is extremely enthusiastic about this research, saying “If this research is successful, we will be able to test, in animal model of autism based on human cells, novel therapeutic approaches and examine those putative therapies on bona fide human cells in an in vivo setting. This is about as close as we can get to clinical trials without actually using humans!”

Dr. Schwartz and his colleague, Dr. Diane O’Dowd, are aiming to build the largest bank of stem cells made from skin (called induced pluripotent stem cells) for autism research.  If these new techniques prove successful, there will be a unique new tool for individualizing autism research unlike any currently available today. Read the grant abstract.

Earlier this year, Antonio Persico, M.D. (Università Campus Bio-Medico di Roma) published results demonstrating that a class of viruses, called polyomaviruses, were found significantly more often in postmortem brain tissue of persons with ASD than in individuals with typical development.  The presence of these viruses presents a possible mechanism for the persistent immune activation seen in brain tissue of individuals with autism, originally reported by Vargas and colleagues in 2005.  How did the viruses get into the brains of these people and what does this mean?  Dr. Persico thinks that at least some forms of autism can be explained by the passing of a virus “vertically”, that is from parent to child, by incorporating itself into the genetic material in the sperm or egg.  The presence of this virus is unknown to the carrier without explicit testing (ie. these individuals do not appear to be acutely ill) and can remain quietly.

Polyomaviruses have been shown to cause autoimmune disorders, which have been correlated with the first degree relatives of individuals with autism. If an early and unresolved polyomavirus infection was present in children with autism, the researchers would expect to see evidence of persistent immune activation for these viruses outside the central nervous system. Indeed, children with autism had lower levels of certain types of polyomavirus in urine than did typically-developing children. These polyomaviruses result in common childhood infections and low levels of virus in children with autism is indirect evidence for immune activation against these specific viruses.  This clue led Dr. Persico and his colleagues to hypothesize that polyomavirus was likely passed from a parent and not acquired later in life.   “What is transmitted from parent to offspring may not be human DNA but rather a virus. This idea could explain high heritability as well as systemic signs and symptoms of ASD, such as overgrowth of the entire body, immune and biochemical abnormalities.  The translational potential of this project in terms of diagnostics, prevention and therapeutics is self-evident,” says Persico. Read the grant abstract.

Taken together, these new grants and the Trailblazer funding mechanism represent a bold new effort to attract and support the most innovative ideas that have the potential to transform our understanding of autism research.  We anxious await to hear from each of these researchers to learn what they discover.

Read a press release about all of the science grants announced by Autism Speaks in December 2010.

Reference:  Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005 Jan;57(1):67-81. Erratum in: Ann Neurol. 2005 Feb;57(2):304.

More mitochondrial dysfunction than expected?

November 30, 2010 45 comments

This Science post is by Staff blogger, Leanne Chukoskie, Ph.D.

Like most parents, the Jensens had little information about the factors that might help explain their son’s autism other than it was compounded by severe and frequent seizures.  When their son was tested, however, they learned that Levi’s cells harbored a mutation that affected the way his cells produced energy.  The Jensens now had valuable information to help treat their son.  For individuals with his particular type of mitochondrial dysfunction, certain seizure medications can cause serious side effects.

In a way, Levi Jensen was lucky. He lived near a large research center that specializes in mitochondrial disorders which is funded by Autism Speaks to investigate the role mitochondria play in autism spectrum disorders (ASD). The diagnosis of mitochondrial disorder or dysfunction is difficult. Multiple tests, often including an invasive muscle biopsy, are required.  How many other individuals with autism might benefit from a deeper understanding of how their cells use energy?

A new study released today in the Journal of the American Medical Association (JAMA) reveals that children with autism may have more trouble fueling the energy demands of their cells due to dysfunctional mitochondria. In this new Autism Speaks-funded study from UC Davis, blood samples from 10 children between the ages 2 and 5 years old and diagnosed with autism were compared with matched control samples from typically developing children.  The investigators found evidence of “breaks” in the cascade of enzymes that mitochondria use to create energy in 8 of 10 autism samples, but no control samples.  They found evidence of a mutation in a gene that supports mitochondrial function, also only in the autism samples. Lastly, in most of the autism samples, there were extra copies of mitochondria. The over-proliferation of mitochondria may also be a sign that individually the mitochondria are not working optimally, and are compensating for reduced function from each mitochondrion by producing more mitochondria overall.

Previous studies have shown that breaks in mitochondrial function can lead to a host of disorders, and the energy-demanding brain can be particularly affected. However, none of the previous autism studies has shown as high a proportion of impaired mitochondrial function as the current study.  Cecilia Giulivi, Ph.D., the lead researcher on the study and a professor of Molecular Biosciences in the School of Veterinary Medicine at UC Davis, was drawn to research abnormal energy metabolism in autism because several symptoms of ASD overlap with mitochondrial diseases.

“We wanted to test the hypothesis in a direct way: is there a mitochondrial dysfunction in material readily available from children with full autism syndrome?” says Giulivi. The research team chose to look at white blood cells—lymphocytes—because they are a type of cell that has significant quantities of mitochondria. Drawing blood is much less invasive than obtaining a muscle biopsy, but traditionally mitochondrial function has been difficult to assess in blood because there are relatively few mitochondria in blood, compared with other body tissues. In fact, red blood cells have no mitochondria at all.

While these results are an exciting new development for both this area of research and for families, it is important to remember that this is still the edge of science and not yet a clinically-useful set of tests. However, if replicated, these tests could make screening for mitochondrial dysfunction much more accessible.

Dr. Giulivi and colleagues are already taking the next steps to follow up this research.  They are studying the families of children with autism to try to understand the mechanism that causes the mitochondrial deficiency. The samples are part of a larger study (CHARGE; Childhood Autism Risks from Genetics and the Environment) in which the investigators are already measuring both genetic and environmental influences on autism risk.  Adding mitochondria to that mix will be especially helpful.  Dr. Giulivi was also quick to add a note of deep appreciation for all the families that participated in the study, saying “Without their participation, we couldn’t have done it!”

Indeed the enthusiasm for research participation often works both ways.  The seizure medication Levi had been taking—Depakote—seemed to make Levi very drowsy. At three years old, Levi was sleeping and napping for 16 hours of the day. His mitochondrial specialist switched medication right away due to concern of an underlying mitochondrial disorder for which Depakote produced severe side effects.

The Jensens are thrilled to report that Levi now has more energy than ever, has regained words that he lost prior to the medication change, and is generally functioning at a much higher level.  For Levi’s parents, Curtis and Alaina Jensen, learning about Levi’s mitochondrial disease helped them gain an understanding of metabolic functions and sparked creative ways to make special considerations for the remaining challenges Levi faced.  Alaina says, “We have found that exercise has been a big key for Levi to feel good and increase his energy and stamina.  It took a long time for him to build up the endurance to play, but it has been worth all the effort.  With a combination of the right seizure medication, supplements, exercise and diet, we now have a very happy boy.”

Click here to view the press release on this new report.

What is mitochondrial disease? How often does it occur in individuals with ASD? Are their effective treatments?

November 9, 2010 8 comments

“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community.  We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.

Cell with LabelsMitochondrial disease is caused by an error in the functioning of mitochondria, which are essential energy-producing compartments of nearly every cell in the body. Certain mutations can cause the mitochondria to function inefficiently. These mutations can be within the mitochondria itself, with its own small circle of DNA, or within the nucleus where the rest of the cell’s DNA resides. Over 1500 genes carry some part of the recipe for the optimal functioning of mitochondria. This means that there are many ways for mitochondria to function imperfectly but there are also complex means available to mask a deficit by altering some of the other protein interactions.

Mitochondria are responsible for the process of oxidative phosphorylation that turns nutrients into energy through a series of stages involving complexes of enzymes. A break at any particular stage results in an atypical balance of metabolites in affected body tissues and fluids.

Most people consider mitochondrial disease to be one of a growing number of disorders caused by a defined set of mutations and presenting with a set of characteristics that typically involve three or more organ systems. However, mitochondrial disorders are often diagnosed when no mutation is found despite observations of metabolic signatures of mitochondrial dysfunction. The symptoms may also be more mild.

We do not have a firm estimate of mitochondrial disease in ASD. However, if we use the broader definition of mitochondrial disorder then according to a population-based study in Portugal, there may be as many as 4% of the ASD population affected. Autism Speaks’ research is addressing this and related questions through a grant to Cecilia Giulivi, Ph.D. at UC Davis and also through a collaborative research project at UC Irvine and UC San Diego.

There is currently no cure for mitochondrial disease or disorder. There are, however, treatments and practices that can improve the quality of life and slow the progression of the disease. The most effective treatments are for specific symptoms that tend to accompany mitochondrial dysfunction such as seizures treated with anti-convulsants. Regular exercise, a healthy diet, stress and extreme temperature avoidance are among the common recommendations. Some dietary and supplement regimes have anecdotal support but there is a need for empirical studies to test the efficacy of these therapies.

For more information, please visit the United Mitochondrial Disease Foundation (UMDF) website. Also, read our report on a joint Autism Speaks’ supported symposium at the annual UMDF meeting.

Mitochondria and Autism Symposium

July 8, 2010 38 comments

For the second year in a row autism was featured at the United Mitochondrial Disease Foundation meeting. Following last year’s well-attended afternoon symposium, Robert Naviaux, M.D., Ph.D. (UCSD), in conjunction with Autism Speaks’ science team, successfully applied for an NIH conference grant to support a more extensive full-day meeting that included a family “Ask the Doc” panel discussion.

Why Mitochondria?

Mitochondria are the primary energy factories for all cells in the body.  When these factories reduce their output, critical cell functions begin to flicker or fade.  The energy is produced through a process called oxidative phosphorylation—an elaborate process that converts oxygen in body tissues to energy used for all cell functions. Although the metaphor of “energy factory” is the most common way to think of mitochondrial function, mitochondria are responsible for much more.  Mitochondria were once — long ago in the history of evolution — single-celled organisms like bacteria that functioned independently, responding to the environment and producing their own proteins encoded by a small circle of DNA.  Several billion years later, mitochondria are fully integrated into our cells, co-opting proteins encoded by the much larger nuclear genome of each cell to serve different functions. Proper mitochondrial function is tuned for each cell type since skin cells, heart cells, and brain cells all have different energy needs.  Mitochondria, like their bacterial predecessors, remain exquisitely sensitive to the local environment and as such function differently in developing versus mature cells, and also in response to differing temperatures, toxins and immune challenges.

Genetics and Epilepsy: finding common ground

The Saturday scientific session began with two primers, one on Autism Spectrum Disorders from Sarah Spence, M.D., Ph.D. (NIMH) and one on mitochondrial disorders from Salvatore DiMauro, M.D. (Columbia University). This background allowed the audience of parents, researchers and clinicians with different specialties to find some common ground for the later presentations and discussion.

One of the unique aspects of this meeting was the pairing of two talks on a topic, one taking the perspective of autism and the other mitochondrial disorders. Abha Gupta, M.D., Ph.D. (Yale) informed the group about our current understanding of autism genetics and focused specifically on what can be learned about the biology of autism by discovering rare mutations. Dr. Naviaux then wove the perspective of traditional mitochondrial genetics into a broader tapestry for the audience to consider. Over 1100 proteins are active in the mitochondria, and the DNA that codes for these proteins is scattered throughout the mitochondrial genome and all the chromosomes in the nuclear genome. This scatter and spread makes mitochondrial function an easy target for random mutations. Also, mutations in one gene can have complex effects on the expression of other genes.

Another area of Dr. Naviaux’s research has focused on a mitochondrial disease called Alper’s syndrome, in which the patient develops typically until a relatively mild viral infection stresses the system and uncovers the mitochondrial deficit, resulting in the onset of severe symptoms. Research into genetic vulnerabilities revealed by environmental stressors is relevant to our understanding in autism of the interaction of genes and the environment. In his presentation, Carlos Pardo, M.D., (Johns Hopkins University) considered the interaction with the immune system by focusing on how components of the immune system serve key roles in development. Dr. Pardo surprised the autism research world in 2005 when he showed clear marks of neuroinflammation—signs of an activated immune system in the brain—using postmortem tissue from individuals with autism. This intersection of immunology and the brain has been a major focus of his lab. At the symposium, Dr. Pardo showed how a specific class of receptors that are important for marshaling resources to fight infection and healthy brain development also affect mitochondrial function. The converse was also noted– the metabolic breakdown products from dysfunctional mitochondria can adversely affect this unique receptor system.

A second set of presentations focused on epilepsy.  Russell Saneto, D.O., Ph.D. (University of Washington) offered his clinical perspective from treating many cases of epilepsy in mitochondrial disorders.  Depending on the underlying cause of epilepsy in mitochondrial disease, different types of treatment tend to be more effective.  This theme was echoed in a presentation from autism expert Roberto Tuchman, M.D. (University of Miami) who talked about “the epilepsies” as a related group of disorders, but noting that optimal treatment comes from identifying underlying biological conditions when possible. A particular type of epilepsy called West syndrome was described by both speakers.  This severe form of epilepsy is thought to involve a dysfunction in a component of neural circuits known as “fast-spiking interneurons” that inhibit the activity of neighboring cells.  These fast-spiking cells are particularly expensive from an energetic perspective.  Therefore, any mitochondrial dysfunction would especially affect these energy-demanding cells.

Carolyn Schanen, M.D., Ph.D.  (University of Delaware) presented data on individuals with autism spectrum disorder that have a duplication in the long arm of chromosome 15. These individuals, who frequently present with epilepsy, exhibit an interesting pattern of gene expression and show evidence of mitochondria dysfunction in postmortem brain tissue. The portrait of this subgroup of autism punctuated the need for pursuing research studies of mitochondrial function in autism and simultaneously highlighting the immediate need for better diagnostic and treatment options.

Diagnosing and treating mitochondrial autism

Richard Haas, M.D. (UCSD) presented the state-of-the-art for diagnosing mitochondrial disorders. The diagnosis of mitochondrial dysfunction is dependent on the results of a series of tests, some of which, like a muscle biopsy or lumbar puncture, are relatively invasive. This presents a situation in which patients and parents need to elect how much testing to do with advice from an informed mitochondrial expert. Although there is no definitive test for mitochondrial disorders, there are agreed-upon checklists based on test results that indicate “likely” or “probably” mitochondrial dysfunction. Dr. Haas pointed to a set of “red flags” that should lead primary care doctors, including pediatricians, to consider a referral to evaluate mitochondrial function.

Treatments for mitochondrial disorders also share a commonality with autism—many complementary and alternative therapies exist with unfortunately little evidence as-of-yet to support their use. Bruce Cohen, D.O., M.D. (Cleveland Clinic) evaluated what we know about vitamin and supplement therapy. Few overall conclusions could be drawn, given the heterogeneity of presentation of mitochondrial dysfunction, but it is clear that more randomized clinical trials are needed especially in subgroups of patients. Until we have more data, exercise is recommended as therapy for all those living with mitochondrial disorders, and certain supplements to support good mitochondrial function and minimize reactive oxygen species may be used under the supervision of a physician to monitor benefit.

Ask the Doc

A group of parents and patients were fortunate to have five leading pediatric neurologists addressing their questions and concerns about mitochondrial disorders and autism. The panelist included Drs. Richard Haas, Sarah Spence, Bruce Cohen, Pauline Filipek, M.D. (University of Texas at Houston) and Roberto Tuchman.

Parents began by asking questions about the prevalence estimates for both autism and mitochondrial disorders, for which we have little population data in the US.  However, the panelists explained that data from a large Portuguese study and several smaller studies would suggest that approximately 5-10% of cases of autism may also have a likely mitochondrial dysfunction.

A lot of discussion centered around the utility of genetic testing, with the panel carefully making the distinction between the need to pursue genetic studies for research but taking caution to not put too much weight on genetic studies for individual diagnostics.  A comparative genomic hybridization (CGH) array study is definitely recommended as a good place to start for suspected mitochondrial disorders.

Questions surrounding treatment were another hot topic.  As noted previously, we would like to get to evidence-based medicine standards for the treatment of autism spectrum and mitochondrial disorders but that is difficult with disorders that present with such unusual heterogeneity.  Among the panelists, there was a general consensus that therapies such as chelation and hyperbaric oxygen were not recommended for this population due to a lack of evidence for positive effects paired with substantial evidence for the potential to harm.  In particular with hyperbaric oxygen therapy, the panelists were concerned about the potential for reactive oxygen species that can emerge from exposing a weakened mitochondrial system to more of what it can’t process well (that is, turning oxygen into energy).  For more innocuous potential therapeutic strategies (such as dietary interventions including some supplements), the panelists suggest that patients (or their parents) work with their physicians to conduct their own trials.  There was great hope for pharmacogenomics in that therapies of the future can be targeted to support a known deficit.

The meeting closed on a note of enthusiasm both for this topic and the pervasive sense of collaboration at this meeting.  Autism Speaks looks forward to more collaboration between our communities for continued progress in understanding and awareness of mitochondrial disorders in autism.


What is Autism to a Mitochondrion?

April 5, 2010 6 comments

This is a guest blog by Jane Pickett, Ph.D. Dr. Pickett has been a pinnacle and founding member of the Autism Tissue Program (ATP), with an unparalleled experience in the field of autism tissue research and brain banking.  Among her duties, Jane stewards the ATP’s vast tissue resources and accumulated data through the ATP Portal, manages the ATP’s large tissue grant portfolio, oversees the TAB and is the direct contact for our supported scientists.  Jane has over 10 years experience serving as coordinator of the Developmental Disability services in Oregon where she participated on the Early Intervention Team, developed and monitored state funded programs for all age groups, provided crisis management for families and facilitated parent support groups.  Her research background includes published studies in molecular and behavioral genetics, neuropeptide biosynthesis, cellular and developmental processes and the role of stress, gender and hormones at Princeton University.  Jane also holds a staff position at the Harvard Brain and Tissue Research Center (HBTRC).

Biologists often try to understand a particular disorder from the perspective of a particular cell, or cell structure.  This was an idea behind a recent public talk, “The Autism Spectrum: Recent Scientific Advances”, by UC Irvine (UCI) medical geneticist Dr. John Jay Gargus.  The link between autism and mitochondria is also the subject of a number of research projects supported by post-mortem brain tissue donated by families to the Autism Tissue Program (ATP).

A mitochondrion is an energy-producing organelle found in cells in the body.  Cells that require a lot of energy (like brain, muscle and liver) have 1000s of mitochondria and others with low energy demand have just a few.  Mitochondria float in the cytoplasm of the cell, outside of the nucleus where the cell’s chromosomes reside.  Each mitochondrion has its own set of 37 genes in a small circular ring of DNA that encode proteins integral for mitochondrial function. However, the mitochondria cannot act entirely alone, depending in part on the production of proteins from some of the genes in the nucleus for full functionality.

Mitochondria combine the fats and sugars we eat with the oxygen we breathe to produce energy for almost all of our cellular needs. If mitochondria are not functioning properly, cells are affected too.  Consider brain cells, highly specialized cells with high energy requirements during their development, migration, maturation and function.  Brain cells called neurons develop processes in order to deliver chemical messages over long distances; sometimes these processes, called axons, are several inches long for a neuron in one side (hemisphere) of the brain to communicate with cells on the other side of the brain.  Mitochondria must provide the energy to ‘build’ these processes, be transported along the axons and once at the junction with other cells (synapses) their functions are necessary to keep up with the demands of brain circuits performing such roles as sensory processing, attention, learning and memory.

Using an electron microscope to get a better look at the fine detail of abnormal-looking mitochondria during neuropathology examination of a post mortem brain, Dr. Jerzy Wegiel at the NY Institute for Basic Research, found ‘osmophilic’ inclusions in the mitochondrial matrix 10 times larger than normal (1). Osmium tetroxide (OsO4) is used as a fixative in preparing histologic specimens and anything in the cell with a high affinity for osmium will have a black appearance. What this structural change means is not clear; generally large inclusions in cell organelles are a sign of a metabolic problem and accumulated waste products.

The donor, age 25, had autism and a chromosome duplication called IDIC15q.  The pathology observed may be linked to a problem with the system of electron carriers that are needed to make energy rich molecules from metabolism in the mitochonrida.  A partial block in the electron-transport chain (respiratory chain) was observed in living persons with autism and IDIC15q by a team working with Dr. Jay Gargus and reported in the journal Mitochrondrion (2).

Muscle hypotonia is common in autism and IDIC15q patients. The energy made by mitochondria provides the main source of power for muscle cell contraction and nerve cell firing so that muscle cells and nerve cells are especially sensitive to mitochondrial defects. The combined effects of energy deprivation contributes to the main symptoms of mitochondrial myopathies and encephalopathies (muscle and brain disorders).  The link between autism and mitochondrial disease is the focus of rigorous study and the subject of one of the top ten research achievements in 2009 (3).

Other mitochondrial abnormalities have been described in brain tissue of individuals with autism. A molecular survey of the tissues of the cortex and cerebellum of brains of individuals  with autism showed a change in the function of a gene, SLC25A12, a key element in mitochondrial energy production and cell metabolism (4).  This gene is important in neurodevelopment and ‘turns on’ early in fetal brain tissue giving rise to a select region associated with early exaggerated postnatal brain growth in children with autism.  A second report on brain genetics from the same French-US group explored another susceptibility locus for autism, a gene called MARK1 (5).  The MARK1 gene product is an enzyme that regulates mitochondrial trafficking along microtubules in neurons: a process which serves as a sort of “highway” within a cell.  Without the right amount of MARK1 produced, mitochondria are likely to be stuck in a “traffic jam” and impair cellular function.  In both studies, the authors discovered an over expression of the two genes in the prefrontal cortex but not in the cerebellum.

So, what is autism to a mitochondrion?  The significance of these findings is that cellular and molecular changes found in the brains of persons with autism are linked to mitochondrial function and are thought to compromise a host of physical and cognitive problems seen in the disorder.  Continued research on the state of mitochondria in autism increases the potential for new diagnostics and therapies.  Brain tissue is important to be able to visualize structural changes as well as to document molecular changes within the cell.

Acknowledgement:  We wish to gratefully recognize the gifts of hope by the families of brain donors.  Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue.  Anyone can register to be a future brain tissue donor. Information can be found at or call toll-free 877-333-0999 for a packet of information, with questions or to initiate a brain donation. Without this partnership between families and scientists, our progress in understanding the underlying biology of autism so effective treatments can be discovered would be much slower.


1.     ATP Informatics Portal, ATP Documents,

2.     Filipek, Pauline A. et al.  (2008) Mitochondrial Dysfunction in Autistic Patients with 15q Inverted Duplication. Mitochondrion 8: 136–145.

3.     Shoffner J, et al. (2009) Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression  J Child Neurol. Sep 22. [Epub ahead of print]

4.     Lepagnol-Bestel AM, et al. (2008) SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal
cortex of autistic subjects. Molecular Psychiatry. 13(4):385-97.

5.     Maussion G, et al.  (2008) Convergent evidence identifying MAP/microtubule affinity regulating kinase 1 (MARK1) as a susceptibility gene for autism. Human Molecular Genetics 17:1-11

Fever Plus Mitochondrial Disease Could Be Risk Factors for Autistic Regression

March 11, 2010 8 comments

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