Evidence linking oxidative stress, mitochondrial dysfunction, and inflammation in the brain of individuals with autism

Daniel A Rossignol, Richard E Frye, Daniel A Rossignol, Richard E Frye

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.

Keywords: autism; brain; inflammation; mitochondrial dysfunction; oxidative stress.

References

    1. Abdallah M. W., Larsen N., Grove J., Norgaard-Pedersen B., Thorsen P., Mortensen E. L., et al. (2013). Amniotic fluid inflammatory cytokines: potential markers of immunologic dysfunction in autism spectr um disorders. World J. Biol. Psychiatry 14, 528–538 10.3109/15622975.2011.639803
    1. Adams J. B., Audhya T., McDonough-Means S., Rubin R. A., Quig D., Geis E., et al. (2011). Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatrics 11:111 10.1186/1471-2431-11-111
    1. Adams J. B., Baral M., Geis E., Mitchell J., Ingram J., Hensley A., et al. (2009). The severity of autism is associated with toxic metal body burden and red blood cell glutathione levels. J. Toxicol. 2009, 1–7 10.1155/2009/532640
    1. Adams J. B., Holloway C. (2004). Pilot study of a moderate dose multivitamin/mineral supplement for children with autistic spectrum disorder. J. Altern. Complement. Med. 10, 1033–1039 10.1089/acm.2004.10.1033
    1. Al-Ayadhi L. Y., Mostafa G. A. (2011). Increased serum osteopontin levels in autistic children: relation to the disease severity. Brain Behav. Immun. 25, 1393–1398 10.1016/j.bbi.2011.04.006
    1. Al-Ayadhi L. Y., Mostafa G. A. (2012). A lack of association between elevated serum levels of S100B protein and autoimmunity in autistic children. J. Neuroinflammation 9, 54 10.1186/1742-2094-9-54
    1. Al-Ayadhi L. Y., Mostafa G. A. (2013). Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children. J. Neuroinflammation 10, 72 10.1186/1742-2094-10-72
    1. Al-Gadani Y., El-Ansary A., Attas O., Al-Ayadhi L. (2009). Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin. Biochem. 42, 1032–1040 10.1016/j.clinbiochem.2009.03.011
    1. Anitha A., Nakamura K., Thanseem I., Matsuzaki H., Miyachi T., Tsujii M., et al. (2013). Downregulation of the expression of mitochondrial electron transport complex genes in autism brains. Brain Pathol. 23, 294–302 10.1111/bpa.12002
    1. Anitha A., Nakamura K., Thanseem I., Yamada K., Iwayama Y., Toyota T., et al. (2012). Brain region-specific altered expression and association of mitochondria-related genes in autism. Mol. Autism 3, 12 10.1186/2040-2392-3-12
    1. APA. (1994). Diagnostic and Statistical Manual of Mental Disorders, 4th Edn. Washington, DC: American Psychiatric Association
    1. Asadabadi M., Mohammadi M. R., Ghanizadeh A., Modabbernia A., Ashrafi M., Hassanzadeh E., et al. (2013). Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial. Psychopharmacology (Berl.) 225, 51–59 10.1007/s00213-012-2796-8
    1. Baio J. (2012). Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1–19
    1. Boris M., Goldblatt A., Galanko J., James S. J. (2004). Association of MTHFR gene variants with autism. J. Am. Phys. Surg. 9, 106–108 Available online at:
    1. Boris M., Kaiser C. C., Goldblatt A., Elice M. W., Edelson S. M., Adams J. B., et al. (2007). Effect of pioglitazone treatment on behavioral symptoms in autistic children. J. Neuroinflammation 4:3 10.1186/1742-2094-4-3
    1. Bowers K., Li Q., Bressler J., Avramopoulos D., Newschaffer C., Fallin M. D. (2011). Glutathione pathway gene variation and risk of autism spectrum disorders. J. Neurodev. Disord. 3, 132–143 10.1007/s11689-011-9077-4
    1. Bradstreet J. J., Smith S., Granpeesheh D., El-Dahr J. M., Rossignol D. (2007). Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Med. Hypotheses 68, 979–987 10.1016/j.mehy.2006.10.015
    1. Burke M. G., Miller M. D. (2011). Practical guidelines for evaluating lead exposure in children with mental health conditions: molecular effects and clinical implications. Postgrad. Med. 123, 160–168 10.3810/pgm.2011.01.2256
    1. Calabrese V., Lodi R., Tonon C., D'Agata V., Sapienza M., Scapagnini G., et al. (2005). Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia. J. Neurol. Sci. 233, 145–162 10.1016/j.jns.2005.03.012
    1. Chauhan A., Audhya T., Chauhan V. (2012a). Brain region-specific glutathione redox imbalance in autism. Neurochem. Res. 37, 1681–1689 10.1007/s11064-012-0775-4
    1. Chauhan A., Chauhan V. (2006). Oxidative stress in autism. Pathophysiology 13, 171–181 10.1016/j.pathophys.2006.05.007
    1. Chauhan A., Gu F., Chauhan V. (2012b). Mitochondrial respiratory chain defects in autism and other neurodevelopmental disorders. J. Pediatr. Biochem. 2, 213–223 10.3233/JPB-120063
    1. Chauhan A., Gu F., Essa M. M., Wegiel J., Kaur K., Brown W. T., et al. (2011). Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. J. Neurochem. 117, 209–220 10.1111/j.1471-4159.2011.07189.x
    1. Chez M. G., Buchanan C. P., Aimonovitch M. C., Becker M., Schaefer K., Black C., et al. (2002). Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J. Child Neurol. 17, 833–837 10.1177/08830738020170111501
    1. Chez M. G., Dowling T., Patel P. B., Khanna P., Kominsky M. (2007). Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children. Pediatr. Neurol. 36, 361–365 10.1016/j.pediatrneurol.2007.01.012
    1. Chugani D. C., Sundram B. S., Behen M., Lee M. L., Moore G. J. (1999). Evidence of altered energy metabolism in autistic children. Prog. Neuropsychopharmacol. Biol. Psychiatry 23, 635–641 10.1016/S0278-5846(99)00022-6
    1. Clark J. B. (1998). N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev. Neurosci. 20, 271–276 10.1159/000017321
    1. Connolly A. M., Chez M. G., Pestronk A., Arnold S. T., Mehta S., Deuel R. K. (1999). Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J. Pediatr. 134, 607–613 10.1016/S0022-3476(99)70248-9
    1. Corrigan N. M., Shaw D. W., Estes A. M., Richards T. L., Munson J., Friedman S. D., et al. (2013). Atypical developmental patterns of brain chemistry in children with autism spectrum disorder. JAMA Psychiatry 70, 964–974 10.1001/jamapsychiatry.2013.1388
    1. Corrigan N. M., Shaw D. W., Richards T. L., Estes A. M., Friedman S. D., Petropoulos H., et al. (2012). Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder. J. Autism Dev. Disord. 42, 105–115 10.1007/s10803-011-1216-y
    1. Dantzer R., O'Connor J. C., Freund G. G., Johnson R. W., Kelley K. W. (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 10.1038/nrn2297
    1. Depino A. M. (2013). Peripheral and central inflammation in autism spectrum disorders. Mol. Cell. Neurosci. 53, 69–76 10.1016/j.mcn.2012.10.003
    1. Dheen S. T., Kaur C., Ling E. A. (2007). Microglial activation and its implications in the brain diseases. Curr. Med. Chem. 14, 1189–1197 10.2174/092986707780597961
    1. Dhillon S., Hellings J. A., Butler M. G. (2011). Genetics and mitochondrial abnormalities in autism spectrum disorders: a review. Curr. Genomics 12, 322–332 10.2174/138920211796429745
    1. Dolske M. C., Spollen J., McKay S., Lancashire E., Tolbert L. (1993). A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 17, 765–774 10.1016/0278-5846(93)90058-Z
    1. Enns G. M. (2003). The contribution of mitochondria to common disorders. Mol. Genet. Metab. 80, 11–26 10.1016/j.ymgme.2003.08.009
    1. Evans T. A., Siedlak S. L., Lu L., Fu X., Wang Z., McGinnis W. R., et al. (2008). The autistic phenotype exhibits a remarkably localized modification of brain protein by products of free radical-induced lipid oxidation. Am. J. Biochem. Biotech. 4, 61–72 10.3844/ajbbsp.2008.61.72
    1. Fahmy S. F., El-hamamsy M. H., Zaki O. K., Badary O. A. (2013). l-Carnitine supplementation improves the behavioral symptoms in autistic children. Res. Autism Spectr. Disord. 7, 159–166 10.1016/j.rasd.2012.07.006
    1. Fernandez-Checa J. C., Garcia-Ruiz C., Colell A., Morales A., Mari M., Miranda M., et al. (1998). Oxidative stress: role of mitochondria and protection by glutathione. Biofactors 8, 7–11 10.1002/biof.5520080102
    1. Fernandez-Checa J. C., Kaplowitz N., Garcia-Ruiz C., Colell A., Miranda M., Mari M., et al. (1997). GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am. J. Physiol. 273(1 Pt 1), G7–G17
    1. Friedman S. D., Shaw D. W., Artru A. A., Richards T. L., Gardner J., Dawson G., et al. (2003). Regional brain chemical alterations in young children with autism spectrum disorder. Neurology 60, 100–107 10.1212/WNL.60.1.100
    1. Frustaci A., Neri M., Cesario A., Adams J. B., Domenici E., Dalla Bernardina B., et al. (2012). Oxidative stress-related biomarkers in autism: systematic review and meta-analyses. Free Radic. Biol. Med. 52, 2128–2141 10.1016/j.freeradbiomed.2012.03.011
    1. Frye R. E. (2012). Biomarkers of abnormal energy metabolism in children with autism spectrum disorder. NAJ Med Sci 5, 141–147 10.7156/v5i3p141
    1. Frye R. E., Delatorre R., Taylor H., Slattery J., Melnyk S., Chowdhury N., et al. (2013a). Redox metabolism abnormalities in autistic children associated with mitochondrial disease. Transl. Psychiatry 3, e273 10.1038/tp.2013.51
    1. Frye R. E., James S. J. (2014). Metabolic pathology of autism in relation to redox metabolism. Biomark. Med. 8, 321–330 10.2217/bmm.13.158
    1. Frye R. E., Melnyk S., Macfabe D. F. (2013b). Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl. Psychiatry 3, e220 10.1038/tp.2012.143
    1. Frye R. E., Naviaux R. K. (2011). Autistic disorder with complex IV overactivity: a new mitochondrial syndrome. J. Pediatr. Neurol. 9, 427–434 10.3233/JPN-2011-0507
    1. Frye R. E., Rossignol D. A. (2011). Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr. Res. 69, 41R–47R 10.1203/PDR.0b013e318212f16b
    1. Frye R. E., Rossignol D. A. (2012a). Mitochondrial and metabolic abnormalities in neurodevelopmental disorders. J. Ped. Biochem. 2, 177–180 10.3233/JPB-120059
    1. Frye R. E., Rossignol D. A. (2012b). Treatments for mitochondrial dysfunction associated with autism spectrum disorders. J Ped Biochem 2, 241–249 10.3233/JPB-120065
    1. Frye R. E., Rossignol D. A. (2013). Mitochondrial physiology and autism spectrum disorder. OA Autism 1, 5 10.13172/2052-7810-1-1-433
    1. Frye R. E., Sequeira J. M., Quadros E. V., James S. J., Rossignol D. A. (2013c). Cerebral folate receptor autoantibodies in autism spectrum disorder. Mol. Psychiatry 18, 369–381 10.1038/mp.2011.175
    1. Garbett K., Ebert P. J., Mitchell A., Lintas C., Manzi B., Mirnics K., et al. (2008). Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol. Dis. 30, 303–311 10.1016/j.nbd.2008.01.012
    1. Geier D. A., Kern J. K., Davis G., King P. G., Adams J. B., Young J. L., et al. (2011). A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders. Med. Sci. Monit. 17, PI15–23 10.12659/MSM.881792
    1. Gesundheit B., Rosenzweig J. P., Naor D., Lerer B., Zachor D. A., Prochazka V., et al. (2013). Immunological and autoimmune considerations of autism spectrum disorders. J. Autoimmun. 44, 1–7 10.1016/j.jaut.2013.05.005
    1. Ghanizadeh A., Moghimi-Sarani E. (2013). A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. BMC Psychiatry 13:196 10.1186/1471-244X-13-196
    1. Ghezzo A., Visconti P., Abruzzo P. M., Bolotta A., Ferreri C., Gobbi G., et al. (2013). Oxidative stress and erythrocyte membrane alterations in children with autism: correlation with clinical features. PLoS ONE 8:e66418 10.1371/journal.pone.0066418
    1. Ginsberg M. R., Rubin R. A., Falcone T., Ting A. H., Natowicz M. R. (2012). Brain transcriptional and epigenetic associations with autism. PLoS ONE 7:e44736 10.1371/journal.pone.0044736
    1. Giulivi C., Zhang Y. F., Omanska-Klusek A., Ross-Inta C., Wong S., Hertz-Picciotto I., et al. (2010). Mitochondrial dysfunction in autism. JAMA 304, 2389–2396 10.1001/jama.2010.1706
    1. Goines P. E., Ashwood P. (2013). Cytokine dysregulation in autism spectrum disorders (ASD): possible role of the environment. Neurotoxicol. Teratol. 36, 67–81 10.1016/j.ntt.2012.07.006
    1. Goin-Kochel R. P., Porter A. E., Peters S. U., Shinawi M., Sahoo T., Beaudet A. L. (2009). The MTHFR 677C–>T polymorphism and behaviors in children with autism: exploratory genotype-phenotype correlations. Autism Res. 2, 98–108 10.1002/aur.70
    1. Golomb B. A., Erickson L. C., Zeeland A. A., Koperski S., Haas R. H., Wallace D. C., et al. (2014). Assessing bioenergetic compromise in autism spectrum disorder with 31P magnetic resonance spectroscopy: preliminary report. J. Child Neurol. 29, 187–193 10.1177/0883073813498466
    1. Gorrindo P., Lane C. J., Lee E. B., McLaughlin B., Levitt P. (2013). Enrichment of elevated plasma F2t-isoprostane levels in individuals with autism who are stratified by presence of gastrointestinal dysfunction. PLoS ONE 8:e68444 10.1371/journal.pone.0068444
    1. Gu F., Chauhan V., Chauhan A. (2013b). Impaired synthesis and antioxidant defense of glutathione in the cerebellum of autistic subjects: alterations in the activities and protein expression of glutathione-related enzymes. Free Radic. Biol. Med. 65C, 488–496 10.1016/j.freeradbiomed.2013.07.021
    1. Gu F., Chauhan V., Kaur K., Brown W. T., Lafauci G., Wegiel J., et al. (2013a). Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism. Transl. Psychiatry 3, e299 10.1038/tp.2013.68
    1. Guevara-Campos J., Gonzalez-Guevara L., Briones P., Lopez-Gallardo E., Bulan N., Ruiz-Pesini E., et al. (2010). Autism associated to a deficiency of complexes III and IV of the mitochondrial respiratory chain. Invest. Clin. 51, 423–431
    1. Guo T., Chen H., Liu B., Ji W., Yang C. (2012). Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genet. Test. Mol. Biomarkers 16, 968–973 10.1089/gtmb.2012.0091
    1. Gupta S., Samra D., Agrawal S. (2010). Adaptive and innate immune responses in autism: rationale for therapeutic use of intravenous immunoglobulin. J. Clin. Immunol. 30 (Suppl 1), S90–S96 10.1007/s10875-010-9402-9
    1. Hardan A. Y., Fung L. K., Libove R. A., Obukhanych T. V., Nair S., Herzenberg L. A., et al. (2012). A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol. Psychiatry 71, 956–961 10.1016/j.biopsych.2012.01.014
    1. Herbert M. R. (2005). Autism: a brain disorder or a disorder that affects the brain. Clin. Neuropsychiatry 2, 354–379 Available online at:
    1. Ipser J. C., Syal S., Bentley J., Adnams C. M., Steyn B., Stein D. J. (2012). 1H-MRS in autism spectrum disorders: a systematic meta-analysis. Metab. Brain Dis. 27, 275–287 10.1007/s11011-012-9293-y
    1. James S. J., Cutler P., Melnyk S., Jernigan S., Janak L., Gaylor D. W., et al. (2004). Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am. J. Clin. Nutr. 80, 1611–1617
    1. James S. J., Melnyk S., Fuchs G., Reid T., Jernigan S., Pavliv O., et al. (2009b). Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am. J. Clin. Nutr. 89, 425–430 10.3945/ajcn.2008.26615
    1. James S. J., Melnyk S., Jernigan S., Cleves M. A., Halsted C. H., Wong D. H., et al. (2006). Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 947–956 10.1002/ajmg.b.30366
    1. James S. J., Melnyk S., Jernigan S., Hubanks A., Rose S., Gaylor D. W. (2008). Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J. Autism Dev. Disord. 38, 1966–1975 10.1007/s10803-008-0591-5
    1. James S. J., Rose S., Melnyk S., Jernigan S., Blossom S., Pavliv O., et al. (2009a). Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB J. 23, 2374–2383 10.1096/fj.08-128926
    1. Khakzad M. R., Javanbakht M., Shayegan M. R., Kianoush S., Omid F., Hojati M., et al. (2012). The complementary role of high sensitivity C-reactive protein in the diagnosis and severity assessment of autism. Res. Autism Spectr. Disord. 6, 1032–1037 10.1016/j.rasd.2011.10.002
    1. Li X., Chauhan A., Sheikh A. M., Patil S., Chauhan V., Li X. M., et al. (2009). Elevated immune response in the brain of autistic patients. J. Neuroimmunol. 207, 111–116 10.1016/j.jneuroim.2008.12.002
    1. López-Hurtado E., Prieto J. J. (2008). A microscopic study of language-related cortex in autism. Am. J. Biochem. Biotech. 4, 130–145 10.3844/ajbbsp.2008.130.145
    1. Lu F., Selak M., O'Connor J., Croul S., Lorenzana C., Butunoi C., et al. (2000). Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J. Neurol. Sci. 177, 95-103 10.1016/S0022-510X(00)00343-9
    1. Mahad D. J., Ziabreva I., Campbell G., Lax N., White K., Hanson P. S., et al. (2009). Mitochondrial changes within axons in multiple sclerosis. Brain 132, 1161–1174 10.1093/brain/awp046
    1. Malik M., Sheikh A. M., Wen G., Spivack W., Brown W. T., Li X. (2011a). Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects. Immunobiology 216, 80–85 10.1016/j.imbio.2010.03.001
    1. Malik M., Tauqeer Z., Sheikh A. M., Wen G., Nagori A., Yang K., et al. (2011b). NF-kappaB signaling in the brain of autistic subjects. Mediat. Inflamm. 2011, 785265 10.1155/2011/785265
    1. Melnyk S., Fuchs G. J., Schulz E., Lopez M., Kahler S. G., Fussell J. J., et al. (2012). Metabolic imbalance associated with methylation dysregulation and oxidative damage in children with autism. J. Autism Dev. Disord. 42, 367–377 10.1007/s10803-011-1260-7
    1. Michel M., Schmidt M. J., Mirnics K. (2012). Immune system gene dysregulation in autism and schizophrenia. Dev. Neurobiol. 72, 1277–1287 10.1002/dneu.22044
    1. Ming X., Brimacombe M., Chaaban J., Zimmerman-Bier B., Wagner G. C. (2008). Autism spectrum disorders: concurrent clinical disorders. J. Child Neurol. 23, 6–13 10.1177/0883073807307102
    1. Ming X., Stein T. P., Brimacombe M., Johnson W. G., Lambert G. H., Wagner G. C. (2005). Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot. Essent. Fatty Acids 73, 379–384 10.1016/j.plefa.2005.06.002
    1. Minshew N. J., Goldstein G., Dombrowski S. M., Panchalingam K., Pettegrew J. W. (1993). A preliminary 31P MRS study of autism: evidence for undersynthesis and increased degradation of brain membranes. Biol. Psychiatry 33, 762–773 10.1016/0006-3223(93)90017-8
    1. Moran M., Moreno-Lastres D., Marin-Buera L., Arenas J., Martin M. A., Ugalde C. (2012b). Mitochondrial respiratory chain dysfunction: implications in neurodegeneration. Free Radic. Biol. Med. 53, 595–609 10.1016/j.freeradbiomed.2012.05.009
    1. Morgan J. T., Chana G., Abramson I., Semendeferi K., Courchesne E., Everall I. P. (2012a). Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res. 1456, 72–81 10.1016/j.brainres.2012.03.036
    1. Morgan J. T., Chana G., Pardo C. A., Achim C., Semendeferi K., Buckwalter J., et al. (2010). Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biol. Psychiatry 68, 368–376 10.1016/j.biopsych.2010.05.024
    1. Mostafa G. A., Al-Ayadhi L. Y. (2012). The relationship between the increased frequency of serum antineuronal antibodies and the severity of autism in children. Eur. J. Paediatr. Neurol. 16, 464–468 10.1016/j.ejpn.2011.12.010
    1. Mostafa G. A., El-Gamal H. A., El-Wakkad A. S. E., El-Shorbagy O. E., Hamza M. M. (2005). Polyunsaturated fatty acids, carnitine and lactate as biological markers of brain energy in autistic children. Int. J. Child Neuropsychiatry 2, 179–188 Available online at:
    1. Mostafa G. A., El-Hadidi E. S., Hewedi D. H., Abdou M. M. (2010). Oxidative stress in Egyptian children with autism: relation to autoimmunity. J. Neuroimmunol. 219, 114–118 10.1016/j.jneuroim.2009.12.003
    1. Mostafa G. A., Kitchener N. (2009). Serum anti-nuclear antibodies as a marker of autoimmunity in Egyptian autistic children. Pediatr. Neurol. 40, 107–112 10.1016/j.pediatrneurol.2008.10.017
    1. Muratore C. R., Hodgson N. W., Trivedi M. S., Abdolmaleky H. M., Persico A. M., Lintas C., et al. (2013). Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism. PLoS ONE 8:e56927 10.1371/journal.pone.0056927
    1. Napoli E., Wong S., Giulivi C. (2013). Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol. Autism 4, 2 10.1186/2040-2392-4-2
    1. Ng F., Berk M., Dean O., Bush A. I. (2008). Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int. J. Neuropsychopharmacol. 11, 851–876 10.1017/S1461145707008401
    1. Nuzzo D., Picone P., Caruana L., Vasto S., Barera A., Caruso C., et al. (2013). Inflammatory mediators as biomarkers in brain disorders. Inflammation. [Epub ahead of print]. 10.1007/s10753-013-9780-2
    1. Onore C., Careaga M., Ashwood P. (2012). The role of immune dysfunction in the pathophysiology of autism. Brain Behav. Immun. 26, 383–392 10.1016/j.bbi.2011.08.007
    1. Palmieri L., Papaleo V., Porcelli V., Scarcia P., Gaita L., Sacco R., et al. (2010). Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol. Psychiatry 15, 38–52 10.1038/mp.2008.63
    1. Poultney C. S., Goldberg A. P., Drapeau E., Kou Y., Harony-Nicolas H., Kajiwara Y., et al. (2013). Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder. Am. J. Hum. Genet. 93, 607–619 10.1016/j.ajhg.2013.09.001
    1. Remels A. H., Gosker H. R., Schrauwen P., Hommelberg P. P., Sliwinski P., Polkey M., et al. (2010). T.N.F-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia? FASEB J. 24, 5052–5062 10.1096/fj.09-150714
    1. Rice C. (2007). Prevalence of autism spectrum disorders–autism and developmental disabilities monitoring network, 14 sites, United States, 2002. MMWR 56, 12–28 Available online at:
    1. Rose S., Melnyk S., Pavliv O., Bai S., Nick T. G., Frye R. E., et al. (2012b). Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl. Psychiatry 2, e134 10.1038/tp.2012.61
    1. Rose S., Melnyk S., Trusty T. A., Pavliv O., Seidel L., Li J., et al. (2012a). Intracellular and extracellular redox status and free radical generation in primary immune cells from children with autism. Autism Res. Treat. 2012, 986519 10.1155/2012/986519
    1. Rossignol D. A. (2009). Novel and emerging treatments for autism spectrum disorders: a systematic review. Ann. Clin. Psychiatry 21, 213–236
    1. Rossignol D. A., Bradstreet J. J. (2008). Evidence of mitochondrial dysfunction in autism and implications for treatment. Am. J. Biochem. Biotech. 4, 208–217 10.3844/ajbbsp.2008.208.217
    1. Rossignol D. A., Frye R. E. (2011). Melatonin in autism spectrum disorders: a systematic review and meta-analysis. Dev. Med. Child Neurol. 53, 783–792 10.1111/j.1469-8749.2011.03980.x
    1. Rossignol D. A., Frye R. E. (2012a). A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol. Psychiatry 17, 389–401 10.1038/mp.2011.165
    1. Rossignol D. A., Frye R. E. (2012b). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol. Psychiatry 17, 290–314 10.1038/mp.2010.136
    1. Rossignol D. A., Frye R. E. (2012c). Substantial problems with measuring brain mitochondrial dysfunction in autism spectrum disorder using magnetic resonance spectroscopy. J. Autism Dev. Disord. 42, 640–642; author reply: 3–6. 10.1007/s10803-011-1276-z
    1. Sajdel-Sulkowska E. M., Lipinski B., Windom H., Audhya T., McGinnis W. R. (2008). Oxidative stress in autism: elevated cerebellar 3-nitrotyrosine levels. Am. J. Biochem. Biotech. 4, 73–84 10.3844/ajbbsp.2008.73.84
    1. Sajdel-Sulkowska E. M., Xu M., Koibuchi N. (2009). Increase in cerebellar neurotrophin-3 and oxidative stress markers in autism. Cerebellum 8, 366–372 10.1007/s12311-009-0105-9
    1. Sajdel-Sulkowska E. M., Xu M., McGinnis W., Koibuchi N. (2011). Brain region-specific changes in oxidative stress and neurotrophin levels in autism spectrum disorders (ASD). Cerebellum 10, 43–48 10.1007/s12311-010-0223-4
    1. Samavati L., Lee I., Mathes I., Lottspeich F., Huttemann M. (2008). Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J. Biol. Chem. 283, 21134–21144 10.1074/jbc.M801954200
    1. Schaefer G. B., Mendelsohn N. J., Professional P., Guidelines C. (2013). Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet. Med. 15, 399–407 10.1038/gim.2013.32
    1. Shao L., Martin M. V., Watson S. J., Schatzberg A., Akil H., Myers R. M., et al. (2008). Mitochondrial involvement in psychiatric disorders. Ann. Med. 40, 281–295 10.1080/07853890801923753
    1. Shenoy S., Arnold S., Chatila T. (2000). Response to steroid therapy in autism secondary to autoimmune lymphoproliferative syndrome. J. Pediatr. 136, 682–687 10.1067/mpd.2000.105355
    1. Shoffner J., Hyams L., Langley G. N., Cossette S., Mylacraine L., Dale J., et al. (2010). Fever plus mitochondrial disease could be risk factors for autistic regression. J. Child Neurol. 25, 429–434 10.1177/0883073809342128
    1. Stefanatos G. A., Grover W., Geller E. (1995). Case study: corticosteroid treatment of language regression in pervasive developmental disorder. J. Am. Acad. Child Adolesc. Psychiatry 34, 1107–1111 10.1097/00004583-199508000-00022
    1. Suematsu N., Tsutsui H., Wen J., Kang D., Ikeuchi M., Ide T., et al. (2003). Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 107, 1418–1423 10.1161/01.CIR.0000055318.09997.1F
    1. Suzuki K., Sugihara G., Ouchi Y., Nakamura K., Futatsubashi M., Takebayashi K., et al. (2013). Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70, 49–58 10.1001/jamapsychiatry.2013.272
    1. Taliou A., Zintzaras E., Lykouras L., Francis K. (2013). An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin. Ther. 35, 592–602 10.1016/j.clinthera.2013.04.006
    1. Tang G., Gutierrez Rios P., Kuo S. H., Akman H. O., Rosoklija G., Tanji K., et al. (2013). Mitochondrial abnormalities in temporal lobe of autistic brain. Neurobiol. Dis. 54, 349–361 10.1016/j.nbd.2013.01.006
    1. Tetreault N. A., Hakeem A. Y., Jiang S., Williams B. A., Allman E., Wold B. J., et al. (2012). Microglia in the cerebral cortex in autism. J. Autism Dev. Disord. 42, 2569–2584 10.1007/s10803-012-1513-0
    1. Theoharides T. C., Asadi S., Panagiotidou S., Weng Z. (2013). The “missing link” in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Autoimmun. Rev. 12, 1136–1142 10.1016/j.autrev.2013.06.018
    1. Trushina E., McMurray C. T. (2007). Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 145, 1233–1248 10.1016/j.neuroscience.2006.10.056
    1. Vali S., Mythri R. B., Jagatha B., Padiadpu J., Ramanujan K. S., Andersen J. K., et al. (2007). Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson's disease: a dynamic model. Neuroscience 149, 917–930 10.1016/j.neuroscience.2007.08.028
    1. van Horssen J., Witte M. E., Ciccarelli O. (2012). The role of mitochondria in axonal degeneration and tissue repair in MS. Mult. Scler. 18, 1058–1067 10.1177/1352458512452924
    1. Vargas D. L., Nascimbene C., Krishnan C., Zimmerman A. W., Pardo C. A. (2005). Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57, 67–81 10.1002/ana.20315
    1. Vempati U. D., Diaz F., Barrientos A., Narisawa S., Mian A. M., Millan J. L., et al. (2007). Role of cytochrome C in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but not with lack of cytochrome C release. Mol. Cell. Biol. 27, 1771–1783 10.1128/MCB.00287-06
    1. Wallace D. C. (1999). Mitochondrial diseases in man and mouse. Science 283, 1482–1488 10.1126/science.283.5407.1482
    1. Wei H., Zou H., Sheikh A. M., Malik M., Dobkin C., Brown W. T., et al. (2011). IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J. Neuroinflammation 8, 52 10.1186/1742-2094-8-52
    1. Weissman J. R., Kelley R. I., Bauman M. L., Cohen B. H., Murray K. F., Mitchell R. L., et al. (2008). Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS ONE 3:e3815 10.1371/journal.pone.0003815
    1. Yao Y., Walsh W. J., McGinnis W. R., Pratico D. (2006). Altered vascular phenotype in autism: correlation with oxidative stress. Arch. Neurol. 63, 1161–1164 10.1001/archneur.63.8.1161
    1. Yorbik O., Sayal A., Akay C., Akbiyik D. I., Sohmen T. (2002). Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins Leukot. Essent. Fatty Acids 67, 341–343 10.1054/plef.2002.0439
    1. Young A. M., Campbell E., Lynch S., Suckling J., Powis S. J. (2011). Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for neuroinflammation. Front. Psychiatry 2:27 10.3389/fpsyt.2011.00027
    1. Zhang B., Angelidou A., Alysandratos K. D., Vasiadi M., Francis K., Asadi S., et al. (2010). Mitochondrial DNA and anti-mitochondrial antibodies in serum of autistic children. J. Neuroinflammation 7, 80 10.1186/1742-2094-7-80
    1. Zimmerman A. W., Jyonouchi H., Comi A. M., Connors S. L., Milstien S., Varsou A., et al. (2005). Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr. Neurol. 33, 195–201 10.1016/j.pediatrneurol.2005.03.014

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