Mitochondrial dysfunction in autism.
TL;DR: There is genetic and biochemical evidence for a mitochondria (mt) role in the pathogenesis of ASD in a subset of children and a need for further research using the latest genetic technology such as next-generation sequencing, microarrays, bioinformatics, and biochemical assays.
About: This article is published in Seminars in Pediatric Neurology.The article was published on 2013-09-01. It has received 213 citations till now. The article focuses on the topics: Respiratory chain & Autism.
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TL;DR: This single clinical report updates the 2007 American Academy of Pediatrics clinical reports on the evaluation and treatment of ASD in one publication with an online table of contents and section view available to help the reader identify topic areas within the report.
Abstract: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with reported prevalence in the United States of 1 in 59 children (approximately 1.7%). Core deficits are identified in 2 domains: social communication/interaction and restrictive, repetitive patterns of behavior. Children and youth with ASD have service needs in behavioral, educational, health, leisure, family support, and other areas. Standardized screening for ASD at 18 and 24 months of age with ongoing developmental surveillance continues to be recommended in primary care (although it may be performed in other settings), because ASD is common, can be diagnosed as young as 18 months of age, and has evidenced-based interventions that may improve function. More accurate and culturally sensitive screening approaches are needed. Primary care providers should be familiar with the diagnosticcriteria for ASD, appropriate etiologic evaluation, and co-occurring medical and behavioral conditions (such as disorders of sleep and feeding, gastrointestinal tract symptoms, obesity, seizures, attention-deficit/hyperactivity disorder, anxiety, and wandering) that affect the child’s function and quality of life. There is an increasing evidence base to support behavioral and other interventions to address specific skills and symptoms. Shared decision making calls for collaboration with families in evaluation and choice of interventions. This single clinical report updates the 2007 American Academy of Pediatrics clinical reports on the evaluation and treatment of ASD in one publication with an online table of contents and section view available through the American Academy of Pediatrics Gateway to help the reader identify topic areas within the report.
582 citations
TL;DR: Results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.
Abstract: Despite increasing evidence of oxidative stress in the pathophysiology of autism, most studies have not evaluated biomarkers within specific brain regions, and the functional consequences of oxidative stress remain relatively understudied. We examined frozen samples from the cerebellum and temporal cortex (Brodmann area 22 (BA22)) from individuals with autism and unaffected controls (n=15 and n=12 per group, respectively). Biomarkers of oxidative stress, including reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione redox/antioxidant capacity (GSH/GSSG), were measured. Biomarkers of oxidative protein damage (3-nitrotyrosine; 3-NT) and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG) were also assessed. Functional indicators of oxidative stress included relative levels of 3-chlorotyrosine (3-CT), an established biomarker of a chronic inflammatory response, and aconitase activity, a biomarker of mitochondrial superoxide production. Consistent with previous studies on plasma and immune cells, GSH and GSH/GSSG were significantly decreased in both autism cerebellum (P<0.01) and BA22 (P<0.01). There was a significant increase in 3-NT in the autism cerebellum and BA22 (P<0.01). Similarly, 8-oxo-dG was significantly increased in autism cerebellum and BA22 (P<0.01 and P=0.01, respectively), and was inversely correlated with GSH/GSSG in the cerebellum (P<0.01). There was a significant increase in 3-CT levels in both brain regions (P<0.01), whereas aconitase activity was significantly decreased in autism cerebellum (P<0.01), and was negatively correlated with GSH/GSSG (P=0.01). Together, these results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.
351 citations
TL;DR: Gut-derived factors, such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can trigger ASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinical medicine.
Abstract: Recent evidence suggests potential, but unproven, links between dietary, metabolic, infective, and gastrointestinal factors and the behavioral exacerbations and remissions of autism spectrum disorders (ASDs). Propionic acid (PPA) and its related short-chain fatty acids (SCFAs) are fermentation products of ASD-associated bacteria (Clostridia, Bacteriodetes, Desulfovibrio). SCFAs represent a group of compounds derived from the host microbiome that are plausibly linked to ASDs and can induce widespread effects on gut, brain, and behavior. Intraventricular administration of PPA and SCFAs in rats induces abnormal motor movements, repetitive interests, electrographic changes, cognitive deficits, perseveration, and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation, increased oxidative stress, glutathione depletion, and altered phospholipid/acylcarnitine profiles. These directly or indirectly contribute to acquired mitochondrial dysfunction via impairment in carnitine-dependent pathways, consistent with findings in patients with ASDs. Of note, common antibiotics may impair carnitine-dependent processes by altering gut flora favoring PPA-producing bacteria and by directly inhibiting carnitine transport across the gut. Human populations that are partial metabolizers of PPA are more common than previously thought. PPA has further bioactive effects on neurotransmitter systems, intracellular acidification/calcium release, fatty acid metabolism, gap junction gating, immune function, and alteration of gene expression that warrant further exploration. These findings are consistent with the symptoms and proposed underlying mechanisms of ASDs and support the use of PPA infusions in rats as a valid animal model of the condition. Collectively, this offers further support that gut-derived factors, such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can trigger ASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinical medicine. Keywords: autism; mitochondria; Clostridia; Desulfovibrio; propionic acid; butyric acid; carnitine; neuroinflammation; oxidative stress; glutathione; gap junctions; microbiome; PUFA; epigenetics (Published: 24 August 2012) Citation: Microbial Ecology in Health & Disease 2012, 23 : 19260 - http://dx.doi.org/10.3402/mehd.v23i0.19260 To access the behavioral videos of propionic acid infusions in rats, click on the links below: A PPA repetitive behavior B control rat C PPA social D control pair social E Ethovision pair F PPA object fixation
347 citations
Cites background from "Mitochondrial dysfunction in autism..."
...Furthermore, a recent study reported that 80% of the children with ASDs showed altered electron transport chain in lymphocytes compared with neurotypic controls (29)....
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TL;DR: The evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals is examined, suggesting that ASD has a clear biological basis with features of known medical disorders.
Abstract: Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that are defined solely on the basis of behavioral observations Therefore, ASD has traditionally been framed as a behavioral disorder However, evidence is accumulating that ASD is characterized by certain physiological abnormalities, including oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation While these abnormalities have been reported in studies that have examined peripheral biomarkers such as blood and urine, more recent studies have also reported these abnormalities in brain tissue derived from individuals diagnosed with ASD as compared to brain tissue derived from control individuals A majority of these brain tissue studies have been published since 2010 The brain regions found to contain these physiological abnormalities in individuals with ASD are involved in speech and auditory processing, social behavior, memory, and sensory and motor coordination This manuscript examines the evidence linking oxidative stress, mitochondrial dysfunction and immune dysregulation/inflammation in the brain of ASD individuals, suggesting that ASD has a clear biological basis with features of known medical disorders This understanding may lead to new testing and treatment strategies in individuals with ASD
276 citations
TL;DR: To understand these "complex" diseases, it is necessary to investigate their bioenergetic pathophysiology and consider the genetics of the thousands of copies of maternally inherited mtDNA, the more than 1,000 nuclear DNA (nDNA)Bioenergetic genes, and the epigenomic and signal transduction systems that coordinate these dispersed elements of the mitochondrial genome.
Abstract: 1405 Origins and implications of human mitochondrial genetics The application of Mendelian genetic principles, using the most sophisticated technologies, has failed to adequately explain the genetics or pathophysiology of many common metabolic and degenerative diseases. This shortcoming can now be understood through the discovery that mutations in the maternally inherited mtDNA can cause many of the symptoms associated with “complex” diseases and that the mtDNA codes for the central genes of the mitochondrial energy–generating process oxidative phosphorylation (OXPHOS). Therefore, the common metabolic and degenerative diseases must be bioenergetic in origin and non-Mendelian in inheritance. The central player in bioenergetics is the mitochondrion. Mitochondria produce about 90% of cellular energy, regulate cellular redox status, produce ROS, maintain Ca 2+ homeostasis, synthesize and degrade high-energy biochemical intermediates, and regulate cell death through activation of the mitochondrial permeability transition pore (mtPTP). The mitochondrial genome consists of thousands of copies of the maternally inherited mtDNA plus between 1,000 and 2,000 nDNA genes. mtDNA codes for 13 OXPHOS polypeptides, plus the 22 transfer RNAs (tRNAs) and the 12S and 16S rRNAs necessary for the bacteria-like mitochondrial protein synthesis. mtDNA polypeptides encompass seven of the 45 polypeptides of OXPHOS complex I (ND1, ND2, ND3, ND4, ND4L, ND5, and ND6), one of the 11 polypeptides of complex III (cytochrome b), three of the 13 polypeptides of complex IV (COI, COII, and COIII), and two of the approximated 17 polypeptides of complex V (ATPase6 and ATPase8). Complexes I, III, and IV constitute the electron transport chain (ETC), which oxidizes the reducing equivalents (hydrogen-derived electrons) from food with the oxygen we breathe. As the electrons flow sequentially through complexes I, III, and IV, protons are pumped out across the mitochondrial inner membrane through these complexes to generate an electrochemical gradient. This mitochondrial capacitor is the vital force and can be used to drive many biological processes, including the condensation of ADP and Pi to form ATP via complex V. Thus oxidation is coupled with phosphorylation in OXPHOS. The 1,000–2,000 nDNA mitochondrial genes, scattered across the chromosomes, code for the remaining approximately 80 OXPHOS subunits, the intermediary metabolism enzymes, and the mitochondrial biogenesis proteins (1–3). Three factors can perturb mitochondrial bioenergetics and result in disease: variation in the mtDNA sequence, variation in the sequences of nDNA-coded mitochondrial genes or in the expression of these genes, or variation in environmental calories and the caloric demands made on the organism. Since different tissues rely on mitochondrial energy to different extents, partial systemic energy deficiency can result in tissue-specific symptoms. The brain, which represents only 2% of the body weight but consumes 20% of the oxygen, is the organ most sensitive to subtle energy diminution. Other high-energy demand tissues include the heart, muscle, kidney, and endocrine system, the organs commonly affected in metabolic and degenerative diseases (Figure 1). mtDNA mutations
250 citations
References
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11 Jun 2013
113,134 citations
TL;DR: It is shown that injury releases mitochondrial DAMPs into the circulation with functionally important immune consequences, including formyl peptides and mitochondrial DNA, which promote PMN Ca2+ flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo.
Abstract: Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.
2,932 citations
"Mitochondrial dysfunction in autism..." refers background in this paper
...ATP is a DAMP.(65) Another reason that a number of mtmolecules act as DAMP is the evolutionary origin of mt as the ancestors of ancient,...
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...ATP is a DAMP.65 Another reason that a number of mtmolecules act as DAMP is the evolutionary origin of mt as the ancestors of ancient, free-living, Gram-negative bacteria.66 The mtDNA itself contains unmethylated CpG dinucleotides that resemble bacterial DNA and activate toll-like receptor 9....
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TL;DR: In this paper, a model that postulates that some forms of autism are caused by an increased ratio of excitation/inhibition in sensory, mnemonic, social and emotional systems is proposed.
Abstract: Autism is a severe neurobehavioral syndrome, arising largely as an inherited disorder, which can arise from several diseases. Despite recent advances in identifying some genes that can cause autism, its underlying neurological mechanisms are uncertain. Autism is best conceptualized by considering the neural systems that may be defective in autistic individuals. Recent advances in understanding neural systems that process sensory information, various types of memories and social and emotional behaviors are reviewed and compared with known abnormalities in autism. Then, specific genetic abnormalities that are linked with autism are examined. Synthesis of this information leads to a model that postulates that some forms of autism are caused by an increased ratio of excitation/inhibition in sensory, mnemonic, social and emotional systems. The model further postulates that the increased ratio of excitation/inhibition can be caused by combinatorial effects of genetic and environmental variables that impinge upon a given neural system. Furthermore, the model suggests potential therapeutic interventions.
2,200 citations
TL;DR: Autism, attention deficit hyperactivity disorder, and other developmental delays increased, whereas hearing loss showed a significant decline, and trends were found in all of the sociodemographic subgroups, except for autism in non-Hispanic black children.
Abstract: OBJECTIVE: To fill gaps in crucial data needed for health and educational planning, we determined the prevalence of developmental disabilities in US children and in selected populations for a recent 12-year period. PARTICIPANTS AND METHODS: We used data on children aged 3 to 17 years from the 1997–2008 National Health Interview Surveys, which are ongoing nationally representative samples of US households. Parent-reported diagnoses of the following were included: attention deficit hyperactivity disorder; intellectual disability; cerebral palsy; autism; seizures; stuttering or stammering; moderate to profound hearing loss; blindness; learning disorders; and/or other developmental delays. RESULTS: Boys had a higher prevalence overall and for a number of select disabilities compared with girls. Hispanic children had the lowest prevalence for a number of disabilities compared with non-Hispanic white and black children. Low income and public health insurance were associated with a higher prevalence of many disabilities. Prevalence of any developmental disability increased from 12.84% to 15.04% over 12 years. Autism, attention deficit hyperactivity disorder, and other developmental delays increased, whereas hearing loss showed a significant decline. These trends were found in all of the sociodemographic subgroups, except for autism in non-Hispanic black children. CONCLUSIONS: Developmental disabilities are common and were reported in ∼1 in 6 children in the United States in 2006–2008. The number of children with select developmental disabilities (autism, attention deficit hyperactivity disorder, and other developmental delays) has increased, requiring more health and education services. Additional study of the influence of risk-factor shifts, changes in acceptance, and benefits of early services is needed.
1,548 citations
"Mitochondrial dysfunction in autism..." refers background in this paper
...74%) individuals, respectively.(6) A recent study by the US Department of Health and Human Services has reported an astonishing prevalence figure of 200 per 10,000 (2%)....
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TL;DR: It is shown that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring and should be identified as a key intermediary in the molecular dissection of the pathways whereby MIA alters fetal brain development.
Abstract: Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.
1,336 citations