{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T09:16:58Z","timestamp":1778059018973,"version":"3.51.4"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T00:00:00Z","timestamp":1498780800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,30]],"date-time":"2017-06-30T00:00:00Z","timestamp":1498780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mitoplasticity occurs when mitochondria adapt to tolerate stressors. Previously we hypothesized that a subset of lymphoblastoid cell lines (LCLs) from children with autistic disorder (AD) show mitoplasticity (AD-A), presumably due to previous environmental exposures; another subset of AD LCLs demonstrated normal mitochondrial activity (AD-N). To better understand mitoplasticity in the AD-A LCLs we examined changes in mitochondrial function using the Seahorse XF96 analyzer in AD and Control LCLs after exposure to trichloroacetaldehyde hydrate (TCAH), an <jats:italic>in vivo<\/jats:italic> metabolite of the environmental toxicant and common environmental pollutant trichloroethylene. To better understand the role of reactive oxygen species (ROS) in mitoplasticity, TCAH exposure was followed by acute exposure to 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases ROS. TCAH exposure by itself resulted in a decline in mitochondrial respiration in all LCL groups. This effect was mitigated when TCAH was followed by acute DMNQ exposure but this varied across LCL groups. DMNQ did not affect AD-N LCLs, while it neutralized the detrimental effect of TCAH in Control LCLs and resulted in a increase in mitochondrial respiration in AD-A LCLs. These data suggest that acute increases in ROS can activate mitochondrial protective pathways and that AD-A LCLs are better able to activate these protective pathways.<\/jats:p>","DOI":"10.1038\/s41598-017-04821-3","type":"journal-article","created":{"date-parts":[[2017,6,26]],"date-time":"2017-06-26T14:08:27Z","timestamp":1498486107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Oxidative Stress Challenge Uncovers Trichloroacetaldehyde Hydrate-Induced Mitoplasticity in Autistic and Control Lymphoblastoid Cell Lines"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4442-2937","authenticated-orcid":false,"given":"Richard Eugene","family":"Frye","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0595-4367","authenticated-orcid":false,"given":"Shannon","family":"Rose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Wynne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sirish C.","family":"Bennuri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Blossom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen M.","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynne","family":"Heilbrun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raymond F.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,6,30]]},"reference":[{"key":"4821_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jaut.2015.11.003","volume":"67","author":"L Matelski","year":"2016","unstructured":"Matelski, L. & Van de Water, J. Risk factors in autism: Thinking outside the brain. J Autoimmun \n                           67, 1\u20137, doi:10.1016\/j.jaut.2015.11.003 (2016).","journal-title":"J Autoimmun"},{"issue":"Suppl 1","key":"4821_CR2","doi-asserted-by":"publisher","first-page":"S232","DOI":"10.1093\/carcin\/bgv038","volume":"36","author":"PA Thompson","year":"2015","unstructured":"Thompson, P. A. et al. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis \n                           36(Suppl 1), S232\u2013253, doi:10.1093\/carcin\/bgv038 (2015).","journal-title":"Carcinogenesis"},{"key":"4821_CR3","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.neuro.2008.02.006","volume":"29","author":"IN Pessah","year":"2008","unstructured":"Pessah, I. N. et al. Immunologic and neurodevelopmental susceptibilities of autism. Neurotoxicology \n                           29, 532\u2013545, doi:10.1016\/j.neuro.2008.02.006 (2008).","journal-title":"Neurotoxicology"},{"key":"4821_CR4","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.fct.2015.11.002","volume":"86","author":"M Hodjat","year":"2015","unstructured":"Hodjat, M., Rezvanfar, M. A. & Abdollahi, M. A systematic review on the role of environmental toxicants in stem cells aging. Food Chem Toxicol \n                           86, 298\u2013308, doi:10.1016\/j.fct.2015.11.002 (2015).","journal-title":"Food Chem Toxicol"},{"key":"4821_CR5","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1089\/ars.2011.4357","volume":"18","author":"C Jose","year":"2013","unstructured":"Jose, C., Melser, S., Benard, G. & Rossignol, R. Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis. Antioxid Redox Signal \n                           18, 808\u2013849, doi:10.1089\/ars.2011.4357 (2013).","journal-title":"Antioxid Redox Signal"},{"key":"4821_CR6","doi-asserted-by":"publisher","first-page":"e360","DOI":"10.1038\/tp.2014.4","volume":"4","author":"DA Rossignol","year":"2014","unstructured":"Rossignol, D. A., Genuis, S. J. & Frye, R. E. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry \n                           4, e360, doi:10.1038\/tp.2014.4 (2014).","journal-title":"Transl Psychiatry"},{"key":"4821_CR7","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.mito.2009.09.006","volume":"10","author":"DC Wallace","year":"2010","unstructured":"Wallace, D. C. & Fan, W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion \n                           10, 12\u201331, doi:10.1016\/j.mito.2009.09.006 (2010).","journal-title":"Mitochondrion"},{"key":"4821_CR8","doi-asserted-by":"publisher","first-page":"41R","DOI":"10.1203\/PDR.0b013e318212f16b","volume":"69","author":"RE Frye","year":"2011","unstructured":"Frye, R. E. & Rossignol, D. A. Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatr Res \n                           69, 41R\u201347R, doi:10.1203\/PDR.0b013e318212f16b (2011).","journal-title":"Pediatr Res"},{"key":"4821_CR9","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/mp.2010.136","volume":"17","author":"DA Rossignol","year":"2012","unstructured":"Rossignol, D. A. & Frye, R. E. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry \n                           17, 290\u2013314, doi:10.1038\/mp.2010.136 (2012).","journal-title":"Mol Psychiatry"},{"key":"4821_CR10","doi-asserted-by":"crossref","unstructured":"Frye, R. E. & Rossignol, D. Mitochondrial physiology and autism spectrum disorder. OA Autism \n                           1 (2013).","DOI":"10.13172\/2052-7810-1-1-433"},{"key":"4821_CR11","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.gene.2005.05.001","volume":"354","author":"DC Wallace","year":"2005","unstructured":"Wallace, D. C. The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene \n                           354, 169\u2013180, doi:10.1016\/j.gene.2005.05.001 (2005).","journal-title":"Gene"},{"key":"4821_CR12","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1289\/ehp.1408418","volume":"122","author":"DT Shaughnessy","year":"2014","unstructured":"Shaughnessy, D. T. et al. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect \n                           122, 1271\u20131278, doi:10.1289\/ehp.1408418 (2014).","journal-title":"Environ Health Perspect"},{"key":"4821_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1427.001","volume":"1147","author":"E Khusnutdinova","year":"2008","unstructured":"Khusnutdinova, E. et al. A mitochondrial etiology of neurodegenerative diseases: evidence from Parkinson\u2019s disease. Ann N Y Acad Sci \n                           1147, 1\u201320, doi:10.1196\/annals.1427.001 (2008).","journal-title":"Ann N Y Acad Sci"},{"key":"4821_CR14","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.taap.2013.03.025","volume":"269","author":"SJ Blossom","year":"2013","unstructured":"Blossom, S. J. et al. Metabolic changes and DNA hypomethylation in cerebellum are associated with behavioral alterations in mice exposed to trichloroethylene postnatally. Toxicol Appl Pharmacol \n                           269, 263\u2013269, doi:10.1016\/j.taap.2013.03.025 (2013).","journal-title":"Toxicol Appl Pharmacol"},{"key":"4821_CR15","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.taap.2011.05.008","volume":"255","author":"AS Bale","year":"2011","unstructured":"Bale, A. S., Barone, S. Jr., Scott, C. S. & Cooper, G. S. A review of potential neurotoxic mechanisms among three chlorinated organic solvents. Toxicol Appl Pharmacol \n                           255, 113\u2013126, doi:10.1016\/j.taap.2011.05.008 (2011).","journal-title":"Toxicol Appl Pharmacol"},{"key":"4821_CR16","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1002\/ana.21288","volume":"63","author":"DM Gash","year":"2008","unstructured":"Gash, D. M. et al. Trichloroethylene: Parkinsonism and complex 1 mitochondrial neurotoxicity. Ann Neurol \n                           63, 184\u2013192, doi:10.1002\/ana.21288 (2008).","journal-title":"Ann Neurol"},{"key":"4821_CR17","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1093\/bja\/45.10.1005","volume":"45","author":"GM Hall","year":"1973","unstructured":"Hall, G. M., Kirtland, S. J. & Baum, H. The inhibition of mitochondrial respiration by inhalational anaesthetic agents. Br J Anaesth \n                           45, 1005\u20131009 (1973).","journal-title":"Br J Anaesth"},{"key":"4821_CR18","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.expneurol.2011.12.012","volume":"234","author":"A Sauerbeck","year":"2012","unstructured":"Sauerbeck, A., Hunter, R., Bing, G. & Sullivan, P. G. Traumatic brain injury and trichloroethylene exposure interact and produce functional, histological, and mitochondrial deficits. Exp Neurol \n                           234, 85\u201394, doi:10.1016\/j.expneurol.2011.12.012 (2012).","journal-title":"Exp Neurol"},{"key":"4821_CR19","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1089\/ars.2011.4033","volume":"16","author":"TN Martinez","year":"2012","unstructured":"Martinez, T. N. & Greenamyre, J. T. Toxin models of mitochondrial dysfunction in Parkinson\u2019s disease. Antioxid Redox Signal \n                           16, 920\u2013934, doi:10.1089\/ars.2011.4033 (2012).","journal-title":"Antioxid Redox Signal"},{"key":"4821_CR20","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1016\/j.neuro.2012.02.017","volume":"33","author":"SJ Blossom","year":"2012","unstructured":"Blossom, S. J., Melnyk, S., Cooney, C. A., Gilbert, K. M. & James, S. J. Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus. Neurotoxicology \n                           33, 1518\u20131527, doi:10.1016\/j.neuro.2012.02.017 (2012).","journal-title":"Neurotoxicology"},{"key":"4821_CR21","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.neuro.2016.01.002","volume":"59","author":"SJ Blossom","year":"2017","unstructured":"Blossom, S. J., Melnyk, S. B., Li, M., Wessinger, W. D. & Cooney, C. A. Inflammatory and oxidative stress-related effects associated with neurotoxicity are maintained after exclusively prenatal trichloroethylene exposure. Neurotoxicology \n                           59, 164\u2013174, doi:10.1016\/j.neuro.2016.01.002 (2017).","journal-title":"Neurotoxicology"},{"key":"4821_CR22","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1093\/toxsci\/kfj212","volume":"92","author":"SJ Blossom","year":"2006","unstructured":"Blossom, S. J. & Gilbert, K. M. Exposure to a metabolite of the environmental toxicant, trichloroethylene, attenuates CD4+ T cell activation-induced cell death by metalloproteinase-dependent FasL shedding. Toxicological sciences: an official journal of the Society of Toxicology \n                           92, 103\u2013114, doi:10.1093\/toxsci\/kfj212 (2006).","journal-title":"Toxicological sciences: an official journal of the Society of Toxicology"},{"key":"4821_CR23","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.intimp.2003.10.001","volume":"4","author":"KM Gilbert","year":"2004","unstructured":"Gilbert, K. M., Whitlow, A. B. & Pumford, N. R. Environmental contaminant and disinfection by-product trichloroacetaldehyde stimulates T cells in vitro. International immunopharmacology \n                           4, 25\u201336, doi:10.1016\/j.intimp.2003.10.001 (2004).","journal-title":"International immunopharmacology"},{"key":"4821_CR24","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.jaut.2004.06.007","volume":"23","author":"SJ Blossom","year":"2004","unstructured":"Blossom, S. J., Pumford, N. R. & Gilbert, K. M. Activation and attenuation of apoptosis of CD4+ T cells following in vivo exposure to two common environmental toxicants, trichloroacetaldehyde hydrate and trichloroacetic acid. J Autoimmun \n                           23, 211\u2013220, doi:10.1016\/j.jaut.2004.06.007 (2004).","journal-title":"J Autoimmun"},{"key":"4821_CR25","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1093\/toxsci\/kfl149","volume":"95","author":"SJ Blossom","year":"2007","unstructured":"Blossom, S. J., Doss, J. C. & Gilbert, K. M. Chronic exposure to a trichloroethylene metabolite in autoimmune-prone MRL+\/+ mice promotes immune modulation and alopecia. Toxicological sciences: an official journal of the Society of Toxicology \n                           95, 401\u2013411, doi:10.1093\/toxsci\/kfl149 (2007).","journal-title":"Toxicological sciences: an official journal of the Society of Toxicology"},{"key":"4821_CR26","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1111\/j.1749-6632.2012.06738.x","volume":"1271","author":"C Kang","year":"2012","unstructured":"Kang, C. & Li, J., L. Role of PGC-1alpha signaling in skeletal muscle health and disease. Ann N Y Acad Sci \n                           1271, 110\u2013117, doi:10.1111\/j.1749-6632.2012.06738.x (2012).","journal-title":"Ann N Y Acad Sci"},{"key":"4821_CR27","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1080\/15287394.2015.958418","volume":"78","author":"HS Yoo","year":"2015","unstructured":"Yoo, H. S. et al. Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: kidney effects. J Toxicol Environ Health A \n                           78, 32\u201349, doi:10.1080\/15287394.2015.958418 (2015).","journal-title":"J Toxicol Environ Health A"},{"key":"4821_CR28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1080\/15287394.2015.958417","volume":"78","author":"HS Yoo","year":"2015","unstructured":"Yoo, H. S. et al. Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: liver effects. J Toxicol Environ Health A \n                           78, 15\u201331, doi:10.1080\/15287394.2015.958417 (2015).","journal-title":"J Toxicol Environ Health A"},{"key":"4821_CR29","doi-asserted-by":"publisher","first-page":"e116179","DOI":"10.1371\/journal.pone.0116179","volume":"9","author":"Y Jiang","year":"2014","unstructured":"Jiang, Y., Chen, J., Tong, J. & Chen, T. Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver. PLoS One \n                           9, e116179, doi:10.1371\/journal.pone.0116179 (2014).","journal-title":"PLoS One"},{"key":"4821_CR30","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.ncl.2011.05.001","volume":"29","author":"F Zaheer","year":"2011","unstructured":"Zaheer, F. & Slevin, J. T. Trichloroethylene and Parkinson disease. Neurol Clin \n                           29, 657\u2013665, doi:10.1016\/j.ncl.2011.05.001 (2011).","journal-title":"Neurol Clin"},{"key":"4821_CR31","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1046\/j.1468-1331.1999.650609.x","volume":"6","author":"D Guehl","year":"1999","unstructured":"Guehl, D. et al. Trichloroethylene and parkinsonism: a human and experimental observation. Eur J Neurol \n                           6, 609\u2013611 (1999).","journal-title":"Eur J Neurol"},{"key":"4821_CR32","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.cppeds.2014.06.001","volume":"44","author":"AE Kalkbrenner","year":"2014","unstructured":"Kalkbrenner, A. E., Schmidt, R. J. & Penlesky, A. C. Environmental chemical exposures and autism spectrum disorders: a review of the epidemiological evidence. Curr Probl Pediatr Adolesc Health Care \n                           44, 277\u2013318, doi:10.1016\/j.cppeds.2014.06.001 (2014).","journal-title":"Curr Probl Pediatr Adolesc Health Care"},{"key":"4821_CR33","unstructured":"Zablotsky, B., Black, L. I., Maenner, M. J., Schieve, L. A. & Blumberg, S. J. Estimated Prevalence of Autism and Other Developmental Disabilities Following Questionnaire Changes in the 2014 National Health Interview Survey. Natl Health Stat Report, 1\u201320 (2015)."},{"key":"4821_CR34","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1001\/archgenpsychiatry.2011.76","volume":"68","author":"J Hallmayer","year":"2011","unstructured":"Hallmayer, J. et al. Genetic heritability and shared environmental factors among twin pairs with autism. Archives of general psychiatry \n                           68, 1095\u20131102, doi:10.1001\/archgenpsychiatry.2011.76 (2011).","journal-title":"Archives of general psychiatry"},{"key":"4821_CR35","doi-asserted-by":"publisher","first-page":"1770","DOI":"10.1001\/jama.2014.4144","volume":"311","author":"S Sandin","year":"2014","unstructured":"Sandin, S. et al. The familial risk of autism. JAMA \n                           311, 1770\u20131777, doi:10.1001\/jama.2014.4144 (2014).","journal-title":"JAMA"},{"key":"4821_CR36","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1289\/ehp.9120","volume":"114","author":"GC Windham","year":"2006","unstructured":"Windham, G. C., Zhang, L., Gunier, R., Croen, L. A. & Grether, J. K. Autism spectrum disorders in relation to distribution of hazardous air pollutants in the san francisco bay area. Environ Health Perspect \n                           114, 1438\u20131444 (2006).","journal-title":"Environ Health Perspect"},{"key":"4821_CR37","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1002\/ajmg.b.30366","volume":"141B","author":"SJ James","year":"2006","unstructured":"James, S. J. et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet \n                           141B, 947\u2013956, doi:10.1002\/ajmg.b.30366 (2006).","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"4821_CR38","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1177\/08830738030180020501","volume":"18","author":"A Evangeliou","year":"2003","unstructured":"Evangeliou, A. et al. Application of a ketogenic diet in children with autistic behavior: pilot study. Journal of child neurology \n                           18, 113\u2013118, doi:10.1177\/08830738030180020501 (2003).","journal-title":"Journal of child neurology"},{"key":"4821_CR39","doi-asserted-by":"publisher","first-page":"e134","DOI":"10.1038\/tp.2012.61","volume":"2","author":"S Rose","year":"2012","unstructured":"Rose, S. et al. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry \n                           2, e134, doi:10.1038\/tp.2012.61 (2012).","journal-title":"Transl Psychiatry"},{"key":"4821_CR40","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/mp.2011.165","volume":"17","author":"DA Rossignol","year":"2012","unstructured":"Rossignol, D. A. & Frye, R. E. 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 \n                           17, 389\u2013401, doi:10.1038\/mp.2011.165 (2012).","journal-title":"Mol Psychiatry"},{"key":"4821_CR41","doi-asserted-by":"publisher","first-page":"e377","DOI":"10.1038\/tp.2014.15","volume":"4","author":"S Rose","year":"2014","unstructured":"Rose, S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry \n                           4, e377, doi:10.1038\/tp.2014.15 (2014).","journal-title":"Transl Psychiatry"},{"key":"4821_CR42","doi-asserted-by":"publisher","first-page":"e85436","DOI":"10.1371\/journal.pone.0085436","volume":"9","author":"S Rose","year":"2014","unstructured":"Rose, S. et al. Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. PLoS One \n                           9, e85436, doi:10.1371\/journal.pone.0085436 (2014).","journal-title":"PLoS One"},{"key":"4821_CR43","doi-asserted-by":"publisher","first-page":"e1405","DOI":"10.1542\/peds.2013-1545","volume":"133","author":"E Napoli","year":"2014","unstructured":"Napoli, E., Wong, S., Hertz-Picciotto, I. & Giulivi, C. Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics \n                           133, e1405\u20131410, doi:10.1542\/peds.2013-1545 (2014).","journal-title":"Pediatrics"},{"key":"4821_CR44","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.1001\/jama.2010.1706","volume":"304","author":"C Giulivi","year":"2010","unstructured":"Giulivi, C. et al. Mitochondrial dysfunction in autism. JAMA \n                           304, 2389\u20132396, doi:10.1001\/jama.2010.1706 (2010).","journal-title":"JAMA"},{"key":"4821_CR45","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1096\/fj.201601004R","volume":"31","author":"S Rose","year":"2017","unstructured":"Rose, S. et al. Mitochondrial and redox abnormalities in autism lymphoblastoid cells: a sibling control study. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           31, 904\u2013909, doi:10.1096\/fj.201601004R (2017).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"4821_CR46","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S0022-510X(00)00343-9","volume":"177","author":"F Lu","year":"2000","unstructured":"Lu, F. et al. Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. Journal of the neurological sciences \n                           177, 95\u2013103 (2000).","journal-title":"Journal of the neurological sciences"},{"key":"4821_CR47","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1093\/brain\/awp046","volume":"132","author":"DJ Mahad","year":"2009","unstructured":"Mahad, D. J. et al. Mitochondrial changes within axons in multiple sclerosis. Brain: a journal of neurology \n                           132, 1161\u20131174, doi:10.1093\/brain\/awp046 (2009).","journal-title":"Brain: a journal of neurology"},{"key":"4821_CR48","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1073\/pnas.0605208103","volume":"104","author":"MI Ekstrand","year":"2007","unstructured":"Ekstrand, M. I. et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA \n                           104, 1325\u20131330, doi:10.1073\/pnas.0605208103 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"4821_CR49","doi-asserted-by":"publisher","first-page":"2374","DOI":"10.1096\/fj.08-128926","volume":"23","author":"SJ James","year":"2009","unstructured":"James, S. J. et al. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           23, 2374\u20132383, doi:10.1096\/fj.08-128926 (2009).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"4821_CR50","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.taap.2013.08.020","volume":"273","author":"G Wang","year":"2013","unstructured":"Wang, G., Wang, J., Ma, H., Ansari, G. A. & Khan, M. F. N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress. Toxicol Appl Pharmacol \n                           273, 189\u2013195, doi:10.1016\/j.taap.2013.08.020 (2013).","journal-title":"Toxicol Appl Pharmacol"},{"key":"4821_CR51","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1006\/bbrc.2001.4577","volume":"282","author":"LX Li","year":"2001","unstructured":"Li, L. X., Skorpen, F., Egeberg, K., Jorgensen, I. H. & Grill, V. Uncoupling protein-2 participates in cellular defense against oxidative stress in clonal beta-cells. Biochemical and biophysical research communications \n                           282, 273\u2013277, doi:10.1006\/bbrc.2001.4577 (2001).","journal-title":"Biochemical and biophysical research communications"},{"key":"4821_CR52","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.bbabio.2007.11.006","volume":"1777","author":"TM Giardina","year":"2008","unstructured":"Giardina, T. M., Steer, J. H., Lo, S. Z. & Joyce, D. A. Uncoupling protein-2 accumulates rapidly in the inner mitochondrial membrane during mitochondrial reactive oxygen stress in macrophages. Biochimica et biophysica acta \n                           1777, 118\u2013129, doi:10.1016\/j.bbabio.2007.11.006 (2008).","journal-title":"Biochimica et biophysica acta"},{"key":"4821_CR53","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/0014-4800(77)90010-7","volume":"27","author":"BA Fowler","year":"1977","unstructured":"Fowler, B. A. & Woods, J. S. Ultrastructural and biochemical changes in renal mitochondria during chronic oral methyl mercury exposure: the relationship to renal function. Experimental and molecular pathology \n                           27, 403\u2013412 (1977).","journal-title":"Experimental and molecular pathology"},{"key":"4821_CR54","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1006\/taap.1999.8652","volume":"157","author":"BJ Shenker","year":"1999","unstructured":"Shenker, B. J. & Guo, T. L. O, I. & Shapiro, I. M. Induction of apoptosis in human T-cells by methyl mercury: temporal relationship between mitochondrial dysfunction and loss of reductive reserve. Toxicol Appl Pharmacol \n                           157, 23\u201335, doi:10.1006\/taap.1999.8652 (1999).","journal-title":"Toxicol Appl Pharmacol"},{"key":"4821_CR55","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1146\/annurev.nutr.17.1.37","volume":"17","author":"RA Goyer","year":"1997","unstructured":"Goyer, R. A. Toxic and essential metal interactions. Annual review of nutrition \n                           17, 37\u201350, doi:10.1146\/annurev.nutr.17.1.37 (1997).","journal-title":"Annual review of nutrition"},{"key":"4821_CR56","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/978-1-4615-0667-6_38","volume":"500","author":"J Pourahmad","year":"2001","unstructured":"Pourahmad, J., Mihajlovic, A. & O\u2019Brien, P. J. Hepatocyte lysis induced by environmental metal toxins may involve apoptotic death signals initiated by mitochondrial injury. Advances in experimental medicine and biology \n                           500, 249\u2013252 (2001).","journal-title":"Advances in experimental medicine and biology"},{"key":"4821_CR57","doi-asserted-by":"crossref","unstructured":"Hiura, T. S. et al. The role of a mitochondrial pathway in the induction of apoptosis by chemicals extracted from diesel exhaust particles. Journal of immunology \n                           165, 2703\u20132711, doi:ji_v165n5p2703 [pii] (2000).","DOI":"10.4049\/jimmunol.165.5.2703"},{"key":"4821_CR58","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1046\/j.1471-4159.2001.00022.x","volume":"76","author":"PW Wong","year":"2001","unstructured":"Wong, P. W., Garcia, E. F. & Pessah, I. N. ortho-substituted PCB95 alters intracellular calcium signaling and causes cellular acidification in PC12 cells by an immunophilin-dependent mechanism. Journal of neurochemistry \n                           76, 450\u2013463 (2001).","journal-title":"Journal of neurochemistry"},{"key":"4821_CR59","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1111\/j.1471-4159.2006.04333.x","volume":"100","author":"TB Sherer","year":"2007","unstructured":"Sherer, T. B. et al. Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson\u2019s disease. Journal of neurochemistry \n                           100, 1469\u20131479, doi:10.1111\/j.1471-4159.2006.04333.x (2007).","journal-title":"Journal of neurochemistry"},{"key":"4821_CR60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF00213961","volume":"28","author":"T Yamano","year":"1995","unstructured":"Yamano, T. & Morita, S. Effects of pesticides on isolated rat hepatocytes, mitochondria, and microsomes II. Archives of environmental contamination and toxicology \n                           28, 1\u20137 (1995).","journal-title":"Archives of environmental contamination and toxicology"},{"key":"4821_CR61","doi-asserted-by":"publisher","first-page":"21134","DOI":"10.1074\/jbc.M801954200","volume":"283","author":"L Samavati","year":"2008","unstructured":"Samavati, L., Lee, I., Mathes, I., Lottspeich, F. & Huttemann, M. Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. The Journal of biological chemistry \n                           283, 21134\u201321144, doi:10.1074\/jbc.M801954200 (2008).","journal-title":"The Journal of biological chemistry"},{"key":"4821_CR62","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1128\/MCB.00287-06","volume":"27","author":"UD Vempati","year":"2007","unstructured":"Vempati, U. D. et al. 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. Molecular and cellular biology \n                           27, 1771\u20131783, doi:10.1128\/MCB.00287-06 (2007).","journal-title":"Molecular and cellular biology"},{"key":"4821_CR63","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1161\/01.CIR.0000055318.09997.1F","volume":"107","author":"N Suematsu","year":"2003","unstructured":"Suematsu, N. et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation \n                           107, 1418\u20131423 (2003).","journal-title":"Circulation"},{"key":"4821_CR64","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/j.neuroscience.2007.08.028","volume":"149","author":"S Vali","year":"2007","unstructured":"Vali, S. et al. Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson\u2019s disease: a dynamic model. Neuroscience \n                           149, 917\u2013930, doi:10.1016\/j.neuroscience.2007.08.028 (2007).","journal-title":"Neuroscience"},{"key":"4821_CR65","doi-asserted-by":"crossref","first-page":"G7","DOI":"10.1152\/ajpcell.1997.273.1.C7","volume":"273","author":"JC Fernandez-Checa","year":"1997","unstructured":"Fernandez-Checa, J. C. et al. GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. The American journal of physiology \n                           273, G7\u201317 (1997).","journal-title":"The American journal of physiology"},{"key":"4821_CR66","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1177\/088307380001500601","volume":"15","author":"WD Graf","year":"2000","unstructured":"Graf, W. D. et al. Autism Associated With the Mitochondrial DNA G8363A Transfer RNALys Mutation. Journal of child neurology \n                           15, 357\u2013361 (2000).","journal-title":"Journal of child neurology"},{"key":"4821_CR67","first-page":"427","volume":"9","author":"RE Frye","year":"2011","unstructured":"Frye, R. E. & Naviaux, R. K. Autistic disorder with complex IV overactivity: A new mitochondrial syndrome. Journal of Pediatric Neurology \n                           9, 427\u2013434 (2011).","journal-title":"Journal of Pediatric Neurology"},{"key":"4821_CR68","doi-asserted-by":"publisher","first-page":"e220","DOI":"10.1038\/tp.2012.143","volume":"3","author":"RE Frye","year":"2013","unstructured":"Frye, R. E., Melnyk, S. & Macfabe, D. F. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder. Transl Psychiatry \n                           3, e220, doi:10.1038\/tp.2012.143 (2013).","journal-title":"Transl Psychiatry"},{"key":"4821_CR69","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/mp.2008.63","volume":"15","author":"L Palmieri","year":"2010","unstructured":"Palmieri, L. et al. Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate\/glutamate carrier AGC1. Mol Psychiatry \n                           15, 38\u201352, doi:10.1038\/mp.2008.63 (2010).","journal-title":"Mol Psychiatry"},{"key":"4821_CR70","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/2040-2392-3-12","volume":"3","author":"A Anitha","year":"2012","unstructured":"Anitha, A. et al. Brain region-specific altered expression and association of mitochondria-related genes in autism. Molecular autism \n                           3, 12, doi:10.1186\/2040-2392-3-12 (2012).","journal-title":"Molecular autism"},{"key":"4821_CR71","doi-asserted-by":"publisher","first-page":"10762","DOI":"10.1523\/JNEUROSCI.4796-14.2015","volume":"35","author":"D Nie","year":"2015","unstructured":"Nie, D. et al. The Stress-Induced Atf3-Gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex. J Neurosci \n                           35, 10762\u201310772, doi:10.1523\/JNEUROSCI.4796-14.2015 (2015).","journal-title":"J Neurosci"},{"key":"4821_CR72","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.1093\/hmg\/ddu101","volume":"23","author":"A Di Nardo","year":"2014","unstructured":"Di Nardo, A. et al. Neuronal Tsc1\/2 complex controls autophagy through AMPK-dependent regulation of ULK1. Hum Mol Genet \n                           23, 3865\u20133874, doi:10.1093\/hmg\/ddu101 (2014).","journal-title":"Hum Mol Genet"},{"key":"4821_CR73","doi-asserted-by":"publisher","first-page":"15276","DOI":"10.1523\/JNEUROSCI.1834-15.2015","volume":"35","author":"AF Bartley","year":"2015","unstructured":"Bartley, A. F. et al. Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus. J Neurosci \n                           35, 15276\u201315290, doi:10.1523\/JNEUROSCI.1834-15.2015 (2015).","journal-title":"J Neurosci"},{"key":"4821_CR74","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/jhg.2012.123","volume":"58","author":"JH Oh","year":"2013","unstructured":"Oh, J. H. et al. Genotype instability during long-term subculture of lymphoblastoid cell lines. Journal of human genetics \n                           58, 16\u201320, doi:10.1038\/jhg.2012.123 (2013).","journal-title":"Journal of human genetics"},{"key":"4821_CR75","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1186\/1471-2164-13-477","volume":"13","author":"D Nickles","year":"2012","unstructured":"Nickles, D. et al. In depth comparison of an individual\u2019s DNA and its lymphoblastoid cell line using whole genome sequencing. BMC genomics \n                           13, 477, doi:10.1186\/1471-2164-13-477 (2012).","journal-title":"BMC genomics"},{"key":"4821_CR76","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1042\/BJ20040485","volume":"382","author":"AJ Lambert","year":"2004","unstructured":"Lambert, A. J. & Brand, M. D. Superoxide production by NADH:ubiquinone oxidoreductase (complex I) depends on the pH gradient across the mitochondrial inner membrane. The Biochemical journal \n                           382, 511\u2013517, doi:10.1042\/BJ20040485 (2004).","journal-title":"The Biochemical journal"},{"key":"4821_CR77","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1042\/BST0371385","volume":"37","author":"DG Nicholls","year":"2009","unstructured":"Nicholls, D. G. Spare respiratory capacity, oxidative stress and excitotoxicity. Biochemical Society transactions \n                           37, 1385\u20131388, doi:10.1042\/BST0371385 (2009).","journal-title":"Biochemical Society transactions"},{"key":"4821_CR78","doi-asserted-by":"publisher","first-page":"7310","DOI":"10.1523\/JNEUROSCI.0212-07.2007","volume":"27","author":"N Yadava","year":"2007","unstructured":"Yadava, N. & Nicholls, D. G. Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. J Neurosci \n                           27, 7310\u20137317, doi:10.1523\/JNEUROSCI.0212-07.2007 (2007).","journal-title":"J Neurosci"},{"key":"4821_CR79","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.cbi.2010.12.002","volume":"191","author":"BE Sansbury","year":"2011","unstructured":"Sansbury, B. E., Jones, S. P., Riggs, D. W., Darley-Usmar, V. M. & Hill, B. G. Bioenergetic function in cardiovascular cells: the importance of the reserve capacity and its biological regulation. Chemico-biological interactions \n                           191, 288\u2013295, doi:10.1016\/j.cbi.2010.12.002 (2011).","journal-title":"Chemico-biological interactions"},{"key":"4821_CR80","doi-asserted-by":"publisher","first-page":"192503","DOI":"10.1155\/2012\/192503","volume":"2012","author":"C Desler","year":"2012","unstructured":"Desler, C. et al. Is There a Link between Mitochondrial Reserve Respiratory Capacity and Aging? Journal of aging research \n                           2012, 192503, doi:10.1155\/2012\/192503 (2012).","journal-title":"Journal of aging research"},{"key":"4821_CR81","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1042\/BJ20090934","volume":"424","author":"BG Hill","year":"2009","unstructured":"Hill, B. G., Dranka, B. P., Zou, L., Chatham, J. C. & Darley-Usmar, V. M. Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal. The Biochemical journal \n                           424, 99\u2013107, doi:10.1042\/BJ20090934 (2009).","journal-title":"The Biochemical journal"},{"key":"4821_CR82","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.freeradbiomed.2010.01.015","volume":"48","author":"BP Dranka","year":"2010","unstructured":"Dranka, B. P., Hill, B. G. & Darley-Usmar, V. M. Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species. Free radical biology & medicine \n                           48, 905\u2013914, doi:10.1016\/j.freeradbiomed.2010.01.015 (2010).","journal-title":"Free radical biology & medicine"},{"key":"4821_CR83","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1111\/j.1471-4159.2009.06055.x","volume":"109","author":"SW Choi","year":"2009","unstructured":"Choi, S. W., Gerencser, A. A. & Nicholls, D. G. Bioenergetic analysis of isolated cerebrocortical nerve terminals on a microgram scale: spare respiratory capacity and stochastic mitochondrial failure. Journal of neurochemistry \n                           109, 1179\u20131191, doi:10.1111\/j.1471-4159.2009.06055.x (2009).","journal-title":"Journal of neurochemistry"},{"key":"4821_CR84","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/S0379-0738(03)00131-2","volume":"134","author":"VA Coopman","year":"2003","unstructured":"Coopman, V. A., Cordonnier, J. A., De Letter, E. A. & Piette, M. H. Tissue distribution of trichloroethylene in a case of accidental acute intoxication by inhalation. Forensic Sci Int \n                           134, 115\u2013119 (2003).","journal-title":"Forensic Sci Int"},{"key":"4821_CR85","first-page":"A61","volume":"1-66","author":"FA Beland","year":"1999","unstructured":"Beland, F. A. NTP technical report on the toxicity and metabolism studies of chloral hydrate (CAS No. 302-17-0). Administered by gavage to F344\/N rats and B6C3F1 mice. Toxic Rep Ser \n                           1\u201366, A61\u2013E67 (1999).","journal-title":"Toxic Rep Ser"},{"key":"4821_CR86","doi-asserted-by":"publisher","first-page":"963","DOI":"10.2307\/2529876","volume":"38","author":"NM Laird","year":"1982","unstructured":"Laird, N. M. & Ware, J. H. Random-effects models for longitudinal data. Biometrics \n                           38, 963\u2013974 (1982).","journal-title":"Biometrics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04821-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04821-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04821-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T06:00:41Z","timestamp":1671775241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-04821-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,30]]},"references-count":86,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["4821"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-04821-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,30]]},"assertion":[{"value":"30 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4478"}}