Mitochondrial Dysfunction in Autism

10 Chronic Diseases linked to mitochondrial dysfunction

Listed below are recent articles and published clinical studies documenting
the strong link between Mitochondrial Dysfunction and Autism.
Neurobiol Dis. 2013 Jan 17
Mitochondrial abnormalities in temporal lobe of autistic brain.
Autism spectrum disorder (ASD) consists of a group of complex developmental disabilities characterized by impaired social interactions, deficits in communication and repetitive behavior. Multiple lines of evidence implicate mitochondrial dysfunction in ASD. In postmortem BA21 temporal cortex, a region that exhibits synaptic pathology in ASD, we found that compared to controls, ASD patients exhibited altered protein levels of mitochondria respiratory chain protein complexes, decreased Complex I and IV activities, decreased mitochondrial antioxidant enzyme SOD2, and greater oxidative DNA damage.
Mitochondrial membrane mass was higher in ASD brain, as indicated by higher protein levels of mitochondrial membrane proteins Tom20, Tim23 and porin. No differences were observed in either mitochondrial DNA or levels of the mitochondrial gene transcription factor TFAM or cofactor PGC1α, indicating that a mechanism other than alterations in mitochondrial genome or mitochondrial biogenesis underlies these mitochondrial abnormalities.
We further identified higher levels of the mitochondrial fission proteins (Fis1 and Drp1) and decreased levels of the fusion proteins (Mfn1, Mfn2 and Opa1) in ASD patients, indicating altered mitochondrial dynamics in ASD brain. Many of these changes were evident in cortical pyramidal neurons, and were observed in ASD children but were less pronounced or absent in adult patients. Together, these findings provide evidence that mitochondrial function and intracellular redox status are compromised in pyramidal neurons in ASD brain and that mitochondrial dysfunction occurs during early childhood when ASD symptoms appear.
Transl Psychiatry 2013 Jan 22
Unique acyl-carnitine profiles are potential biomarkers for
acquired mitochondrial disease in autism spectrum disorder.
Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD.
Acquired mitochondrial disease (MD) has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism.....
Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of mitochondrial metabolism revealed a pattern consistent with the notion that PPA could be interfering with mitochondrial metabolism at the level of the tricarboxylic-acid cycle (TCAC). The function of the fatty-acid oxidation pathway in fibroblast cultures and biomarkers for abnormalities in non-mitochondrial fatty-acid metabolism were not consistently abnormal across the subgroup of ASD children, consistent with the notion that the abnormalities in fatty-acid metabolism found in this subgroup of children with ASD were secondary to TCAC abnormalities. Glutathione metabolism was abnormal in the subset of ASD individuals with consistent acyl-carnitine panel abnormalities in a pattern similar to glutathione abnormalities found in the PPA rodent model of ASD. These data suggest that there are similar pathological processes between a subset of ASD children and an animal model of ASD with acquired mitochondrial dysfunction.
Future studies need to identify additional parallels between the PPA rodent model of ASD and this subset of ASD individuals with this unique pattern of acyl-carnitine abnormalities. A better understanding of this animal model and subset of children with ASD should lead to better insight in mechanisms behind environmentally induced ASD pathophysiology and should provide guidance for developing preventive and symptomatic treatments.
Cell J. 2012
Investigation of the Mitochondrial ATPase 6/8
and tRNA(Lys) Genes Mutations in Autism.
OBJECTIVE: Autism results from developmental factors that affect many or all functional brain systems. Brain is one of tissues which are crucially in need of adenosine triphosphate (ATP). Autism is noticeably affected by mitochondrial dysfunction which impairs energy metabolism. Considering mutations within ATPase 6, ATPase 8 and tRNA(Lys) genes, associated with different neural diseases, and the main role of ATPase 6/8 in energy generation, we decided to investigate mutations on these mtDNA-encoded genes to reveal their roles in autism pathogenesis.
MATERIALS AND METHODS: In this experimental study, mutation analysis for the mentioned genes were performed in a cohort of 24 unrelated patients with idiopathic autism by employing amplicon sequencing of mtDNA fragments.
RESULTS: In this study, 12 patients (50%) showed point mutations that represent a significant correlation between autism and mtDNA variations. Most of the identified substitutions (55.55%) were observed on MT-ATP6, altering some conserved amino acids to other ones which could potentially affect ATPase 6 function. Mutations causing amino acid replacement denote involvement of mtDNA genes, especially ATPase 6 in autism pathogenesis.
CONCLUSION: MtDNA mutations in relation with autism could be remarkable to realize an understandable mechanism of pathogenesis in order to achieve therapeutic solutions.
Brain Pathol. 2012 Oct 23
Downregulation of the Expression of Mitochondrial
Electron Transport Complex Genes in Autism Brains.
Mitochondrial dysfunction (MtD) and abnormal brain bioenergetics have been implicated in autism, suggesting possible candidate genes in the electron transport chain (ETC). We compared the expression of 84 ETC genes in the post-mortem brains of autism patients and controls. Brain tissues from the anterior cingulate gyrus, motor cortex, and thalamus of autism patients (n = 8) and controls (n = 10) were obtained from Autism Tissue Program, USA. Quantitative real-time PCR arrays were used to quantify gene expression.
We observed reduced expression of several ETC genes in autism brains compared to controls. Eleven genes of Complex I, five genes each of Complex III and Complex IV, and seven genes of Complex V showed brain region-specific reduced expression in autism. ATP5A1 (Complex V), ATP5G3 (Complex V) and NDUFA5 (Complex I) showed consistently reduced expression in all the brain regions of autism patients. Upon silencing ATP5A1, the expression of mitogen-activated protein kinase 13 (MAPK13), a p38 MAPK responsive to stress stimuli, was upregulated in HEK 293 cells. This could have been induced by oxidative stress due to impaired ATP synthesis. We report new candidate genes involved in abnormal brain bioenergetics in autism, supporting the hypothesis that mitochondria, critical for neurodevelopment, may play a role in autism.
Mol Psychiatry. 2012 Mar;
Mitochondrial dysfunction in autism spectrum disorders:
a systematic review and meta-analysis.
A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations:

ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (≈ 0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD.

Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD.

Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.

Mitochondrial Dysfunction Linked to Autism
January 31, 2011 — Mitochondrial dysfunction (MD) is more common in children with autism and autism spectrum disorder (ASD) than the general population, a comprehensive systematic review and meta-analysis of relevant research confirms.
Mitochondrial dysfunction "may play a significant role in contributing to the symptoms of autism and is generally underrecognized in these children," Daniel A. Rossignol, MD, of the International Child Development Resource Center, Melbourne, Florida, told Medscape Medical News.
Dr. Daniel A. Rossignol 
"Testing for mitochondrial dysfunction is available, and early treatment might lead to better long-term developmental outcomes," said Dr. Rossignol, who coauthored the review with Richard E. Frye, MD, PhD, of the University of Texas in Houston.
The report was published online January 25 in Molecular Psychiatry.
Commenting on the study Cecilia Giulivi, PhD, professor of biochemistry and metabolic regulation, at the University of California, Davis, who was not involved in the analysis, said, "At this point, it looks like there is a higher incidence of mitochondrial disease in autism, much higher than we suspected."
She noted, however, that testing for MD "is not a trivial task [and] we need more research to come up with a consensus of diagnostic tests to run. In addition, maybe other metabolic syndromes should be looked into," Dr. Giulivi said.
The primary objectives of the analysis were to identify features of MD in the general population of children with ASD and compare characteristics of MD in children with ASD and concomitant significant and severe MD with that of ASD children without MD and non-ASD children with MD.
They included 68 relevant published articles in a qualitative synthesis, including 18 studies with a total of 112 children with ASD and MD.
Genetics Not the Culprit
The results showed the prevalence of MD in the general population of children with ASD is approximately 5% (95% confidence interval [CI], 3.2% – 6.9%), which is 500% higher than the general population prevalence of 0.01%. For a variety of reasons, "this 5% value is most likely an underestimation," Dr. Rossignol said.
It also appears that one-third or more of children with autism may have some type of dysfunction in their mitochondria. On the basis of laboratory testing, the prevalence of abnormal biomarker values of MD, including lactate, pyruvate, carnitine, and ubiquinone, was high in children with ASD, much higher than the prevalence of MD. Some of these markers correlated with the severity of ASD.
Most of the 112 children with ASD and MD (79%) had no identifiable genetic abnormality that could account for the MD.
"The mitochondrial dysfunction and disease reported in autism are related to a genetic abnormality in only 1 out of 5 children; meaning that a majority of these children have something else contributing to this dysfunction, which might include multiple environmental factors, such as toxins, oxidative stress, inflammation, and decreased levels of antioxidants," said Dr. Rossignol.
"Clearly, mitochondrial function is a ripe area of research when investigating the biological mechanism(s) of action of environmental toxicant exposures and indigenous abnormalities associated with ASD," the study authors write.
Loss of Social Skills
Children with ASD and MD had some distinct characteristics compared with the general population of children with ASD. In 12 studies, "children with autism and mitochondrial problems were more likely to lose acquired skills compared to children with autism in general," said Dr. Rossignol. However, it was not clear whether MD contributed to or caused the reported regression.
In addition to a higher prevalence of developmental regression (52%), seizures (41%), motor delay (51%), and gastrointestinal abnormalities (74%), such as reflux and constipation, also appear to be significantly more common in children with ASD and MD relative to children with just ASD.
Currently, "testing for mitochondrial problems in children with autism is rarely done, and we feel that testing should be routine, especially in children with regression or loss of skills," said Dr. Rossignol. "This is important because early recognition of mitochondrial problems in autism might lead to better outcomes in children with autism."
Dr. Rossignol and Dr. Frye note in their report that published studies looking at treatment for ASD and MD are limited. However, some studies have suggested that treatment with mitochondrial cofactor supplementation, including antioxidants, carnitine, coenzyme Q10, and B vitamins, may improve mitochondrial function and behavior in some children with ASD.
"A therapeutic trial of mitochondrial cofactors and antioxidants may be reasonable in children with ASD/MD," the study authors conclude. Carnitine, they say, may be particularly helpful in children with ASD because carnitine deficiency has been implicated in ASD, and some studies have reported improvements with the use of carnitine in ASD.
The researchers emphasize, however, that systematic studies documenting the efficacy of this and other potential treatments for MD in children with ASD are generally lacking.
Children With Autism Have Mitochondrial Dysfunction, Study Finds
Nov. 30, 2010 — Children with autism are far more likely to have deficits in their ability to produce cellular energy than are typically developing children, a new study by researchers at UC Davis has found. The study, published in the Journal of the American Medical Association (JAMA), found that cumulative damage and oxidative stress in mitochondria, the cell's energy producer, could influence both the onset and severity of autism, suggesting a strong link between autism and mitochondrial defects.
After the heart, the brain is the most voracious consumer of energy in the body. The authors propose that deficiencies in the ability to fuel brain neurons might lead to some of the cognitive impairments associated with autism. Mitochondria are the primary source of energy production in cells and carry their own set of genetic instructions, mitochondrial DNA (mtDNA), to carry out aerobic respiration. Dysfunction in mitochondria already is associated with a number of other neurological conditions, including Parkinson's disease, Alzheimer's disease, schizophrenia and bipolar disorder.
"Children with mitochondrial diseases may present exercise intolerance, seizures and cognitive decline, among other conditions. Some will manifest disease symptoms and some will appear as sporadic cases," said Cecilia Giulivi, the study's lead author and professor in the Department of Molecular Biosciences in the School of Veterinary Medicine at UC Davis. "Many of these characteristics are shared by children with autism."
The researchers stress that these new findings, which may help physicians provide early diagnoses, do not identify the cause or the effects of autism, which affects as many as 1 in every 110 children in the United States, according to the U.S. Centers for Disease Control and Prevention.
While previous studies have revealed hints of a connection between autism and mitochondrial dysfunction, these reports have been either anecdotal or involved tissues that might not be representative of neural metabolism.
"It is remarkable that evidence of mitochondrial dysfunction and changes in mitochondrial DNA were detected in the blood of these young children with autism," said Geraldine Dawson, chief science officer of Autism Speaks, which provided funding for the study. "One of the challenges has been that it has been difficult to diagnose mitochondrial dysfunction because it usually requires a muscle biopsy. If we could screen for these metabolic problems with a blood test, it would be a big step forward."
Here is the published Study
JAMA. 2010;
Mitochondrial Dysfunction in Autism
Context:  Impaired mitochondrial function may influence processes highly dependent on energy, such as neurodevelopment, and contribute to autism. No studies have evaluated mitochondrial dysfunction and mitochondrial DNA (mtDNA) abnormalities in a well-defined population of children with autism.
Objective:  To evaluate mitochondrial defects in children with autism.
Design, Setting, and Patients:  Observational study using data collected from patients aged 2 to 5 years who were a subset of children participating in the Childhood Autism Risk From Genes and Environment study in California, which is 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. Mitochondrial dysfunction and mtDNA abnormalities were evaluated in lymphocytes from 10 children with autism and 10 controls.
Main Outcome Measures:  Oxidative phosphorylation capacity, mtDNA copy number and deletions, mitochondrial rate of hydrogen peroxide production, and plasma lactate and pyruvate.
Results:  The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity (normalized to citrate synthase activity) in lymphocytic mitochondria from children with autism was significantly lower compared with controls (mean, 4.4 [95% confidence interval {CI}, 2.8-6.0] vs 12 [95% CI, 8-16], respectively; P = .001). The majority of children with autism (6 of 10) had complex I activity below control range values. (PdLA Complex can specifically increase Complex1 Activity)
Higher plasma pyruvate levels were found in children with autism compared with controls (0.23 mM [95% CI, 0.15-0.31 mM] vs 0.08 mM [95% CI, 0.04-0.12 mM], respectively; P = .02). (This could be due to increase HIF-1 Levels due to Hypoxia........per the last email I sent to you from Johns Hopkins. PDK protein is binding with PDH and preventing the breakdown of Pyruvate into Acetyl-CoA........thus there are higher levels of pyruvate.)
Eight of 10 cases had higher pyruvate levels but only 2 cases had higher lactate levels compared with controls. These results were consistent with the lower pyruvate dehydrogenase activity observed in children with autism compared with controls (1.0 [95% CI, 0.6-1.4] nmol × [min × mg protein]−1 vs 2.3 [95% CI, 1.7-2.9] nmol × [min × mg protein]−1, respectively; P = .01). (Same reason as above)
Children with autism had higher mitochondrial rates of hydrogen peroxide production compared with controls (0.34 [95% CI, 0.26-0.42] nmol × [min × mg of protein]−1 vs 0.16 [95% CI, 0.12-0.20] nmol × [min × mg protein]−1 by complex III; P = .02). (PdLA complex reverses hydrogen peroxide production)