Cited by 168Mitochondrial Function and PathologyAutism Spectrum Disorder ResearchAutophagy in Disease and Therapy

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Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort

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Rose, Shannon, Frye, Richard E., Slattery, John, Wynne, Rebecca, Tippett, Marie, Pavliv, Oleksandra, Melnyk, Stepan, James, S. Jill·2014·PLoS ONE

DOI 10.1371/journal.pone.0085436PMC PMC3885720

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Abstract

There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases intracellular reactive oxygen species (ROS). Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32%) of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxicants. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.

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Figure 1 The Seahorse assay. Oxygen consumption rate (OCR) is measured before and after the addition of inhibitors to derive several parameters of mitochondrial respiration. Initially, baseline cellular OCR is measured, from which basal respiration can be derived by subtracting non-mitochondrial respiration. Next oligomycin, a complex V inhibitor, is added and the resulting OCR is used to derive ATP-linked respiration (by subtracting the oligomycin rate from baseline cellular OCR) and proton leak respiration (by subtracting non-mitochondrial respiration from the oligomycin rate). Next carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazon (FCCP), a protonophore, is added to collapse the inner membrane gradient, allowing the ETC to function at its maximal rate, and maximal respiratory capacity is derived by subtracting non-mitochondrial respiration from the FCCP rate. Lastly, antimycin A and rotenone, inhibitors of complex III and I, are added to shut down ETC function, revealing the non-mitochondrial respiration. Mitochondrial reserve capacity is calculated by subtracting basal respiration from maximal respiratory capacity.CC BY · PubMed Central

Figure 2 AD LCLs demonstrate differences in mitochondrial function as compared to control LCLs at baseline and after exposure to DMNQ. (A) ATP-linked respiration and (B) proton leak respiration were overall significantly higher in the AD LCLs, and there was a greater increase in proton leak respiration with DMNQ as compared to control LCLs. (C) Maximal respiratory capacity was significantly elevated in the AD LCLs at 0 µM and 5 µM DMNQ compared to control LCLs, and the AD LCLs exhibited a greater decrease in maximal capacity as DMNQ increased as compared to control LCLs. (D) Reserve capacity was significantly elevated in the AD LCLs at baseline, and it decreased with DMNQ so that it was significantly lower than control LCLs at 10–15 µM DMNQ. *p<0.001; **p<0.0001; ↕ indicates an overall statistical difference between LCL groups.CC BY · PubMed Central

Figure 3 The AD LCLs cluster into two subgroups. The difference in baseline reserve capacity between control and AD pairs was plotted against the difference in the change in reserve capacity (from 0 to 10 µM DMNQ) between control and AD pairs. The AD-A subgroup (green diamonds) exhibited greater differences in baseline reserve capacity and change in reserve capacity as compared to the paired control LCLs, whereas the AD-N subgroup (orange circles) exhibited reserve capacity parameters more similar to the paired control LCLs.CC BY · PubMed Central

Figure 4 Mitochondrial respiratory parameters and responses to DMNQ differ in two AD LCL subgroups. Overall, the AD-N subgroup (A–D) demonstrates similar mitochondrial responses as the control LCLs while the AD-A subgroup (E–H) parallels the differences between the AD and control LCLs found in the overall analysis. For the AD-N subgroup (A) ATP-linked respiration and (D) reserve capacity were overall slightly but significantly lower in the AD-N LCLs while (B) proton leak respiration was overall slightly but significantly higher in the AD-N LCLs, and (C) maximal respiratory capacity was not different in the AD-N LCLs as compared to controls. For the AD-A subgroup, (E) ATP-linked respiration, (F) proton leak respiration and (G) maximal respiratory capacity were overall markedly higher for AD-A LCLs as compared to control LCLs. (H) Reserve capacity was significantly greater for the AD-A LCLs as compared to control LCLs at baseline but decreased such that it was significantly lower than controls at 10–15 µM DMNQ. (I) ATP-linked respiration was overall markedly higher for AD-A LCLs as compared to AD-N LCLs. (J) Proton leak respiration was significantly higher in the AD-A LCLs as compared to the AD-N LCLs at 5–15 µM DMNQ. (K) Maximal respiratory capacity was significantly higher for AD-A LCLs as compared to AD-N LCLs at baseline and 5 µM DMNQ. (L) Reserve capacity was significantly greater for the AD-A LCLs at baseline but decreased so that it was significantly lower for the AD-A LCLs as compared to the AD-N LCLs at 12.5 and 15 µM DMNQ. *p<0.001; **p<0.0001; # p<0.01; p<0.05; ↕ indicates an overall statistical difference between LCL groups.CC BY · PubMed Central

Figure 5 Extracellular acidification rate (ECAR) differs in AD-A and AD-N LCLs. Basal ECAR was overall significantly higher, and the decrease in ECAR with DMNQ was also greater for the (A) AD LCLs as a whole, (B) the AD-N LCLs and (C) the AD-A LCLs as compared to matched controls. (D) The AD-A LCLs had an overall significantly higher basal ECAR than the AD-N LCLs. (E) Glycolytic reserve capacity was overall higher in the AD LCLs as a whole compared to the control LCLs, but was not different between (F) AD-N and controls. (G) The AD-A LCLs exhibited overall higher glycolytic reserve capacity as compared to the control LCLs and compared to the (H) AD-N LCLs. *p<0.001; **p<0.0001; ↕ indicates an overall statistical difference between LCL groups.CC BY · PubMed Central

Figure 6 Inhibition of UCP2 with Genipin affects AD-A and AD-N LCLs differently. (A) ATP-linked respiration was overall higher in LCLs exposed to genipin compared to unexposed LCLs, and cells exposed to genipin exhibited a greater increase in ATP-linked respiration with DMNQ compared to cells unexposed to genipin. (B) Proton leak respiration was overall higher in the LCLs exposed to genipin as compared to the unexposed LCLs, and pretreatment with genipin resulted in a greater increase in proton leak respiration for the AD-N LCLs as compared to the AD-A LCLs. LCLs exposed to genipin had a greater increase in proton leak respiration with DMNQ compared to cells unexposed to genipin. (C) Maximal respiratory capacity was overall higher in the LCLs exposed to genipin than the LCLs not exposed to genipin, and the decrease in maximal capacity with DMNQ was greater for the genipin treated LCLs compared to the genipin unexposed LCLs. (D) Reserve capacity was overall higher in the LCLs exposed to genipin as compared to the unexposed LCLs, and the increase in reserve capacity with genipin was greater for the AD-A LCLs than the AD-N LCLs. The decrease in reserve capacity with DMNQ was significantly greater for the genipin treated LCLs as compared to the genipin unexposed cells.CC BY · PubMed Central

Figure 7 UCP2 content is higher in the AD-A LCL subgroup. (A) Immunoblot analysis of UCP2. Cell lysates from AD-N LCLs (N = 4) and AD-A LCLs (N = 6) were analyzed for UCP2 content. A total protein stain served as the loading control. The molecular weight of UCP2 was confirmed using molecular mass markers. (B) Quantitation of band densities demonstrates the significantly higher UCP2 content in AD-A LCLs as compared to AD-N LCLs. *p<0.01.CC BY · PubMed Central

Figure 8 Mitochondrial DNA copy number does not differ between AD LCL subgroups. Relative copy numbers of the mitochondrial genes ND1, ND4, and Cyt B were assessed by normalization with the nuclear gene PK. No significant differences were found between two AD LCL subgroups.CC BY · PubMed Central

Figure 9 DMNQ exposure alters the glutathione redox status of LCLs. The change in intracellular (A) reduced glutathione (GSH), (B) oxidized glutathione (GSSG) and (C) the reduced-to-oxidized glutathione ratio (GSH/GSSG) with increased intracellular oxidative stress was measured in control (n = 3) and AD (n = 5) LCLs treated with indicated concentrations of the redox cycling agent DMNQ for 1 h. Results are expressed per mg protein. Overall DMNQ significantly reduces GSH and GSH/GSSH and increases GSSG.CC BY · PubMed Central

Figure 10 AD LCLs exhibit a more oxidized redox state and increased production of ROS. (A) Reduced glutathione (GSH) and the reduced-to-oxidized glutathione ratio (GSH/GSSG) were both significantly lower in AD as compared to control LCLs. (B) The ratio of reduced cysteine to oxidized cystine was significantly lower in the AD LCLs as compared to the control LCLs. The NADH/NAD+ ratio was also significantly lower in the AD LCLs as compared to control LCLs. The data is presented as the NADH/NAD+ ratio x 10 for clarity. (C) 3-nitrotyrosine was significantly higher in the AD LCLs as compared to the control LCLs. (D) Intracellular ROS was measured by CellRox Green fluorescence, and the AD LCLs demonstrated significantly higher levels of intracellular ROS as compared to control LCLs. Furthermore, the AD-A LCLs demonstrated higher levels of intracellular ROS as compared to the AD-N LCLs. (E) Mitochondrial superoxide was measured using MitoSox Red fluorescence, and (F) mitochondrial membrane potential was measured using JC-1 fluorescence in the AD and control LCLs. There were no significant differences in either mitochondrial superoxide or mitochondrial membrane potential between any of the LCL groups. *p<0.01; **p<0.05.CC BY · PubMed Central

Figure 11 Normal adaptive and maladaptive mitochondrial responses to a more oxidized intracellular microenvironment. Diagrammed are the normal adaptive (AD-N) and maladaptive (AD-A) responses to a more highly oxidized intracellular microenvironment in the AD LCLs. The normal adaptive response of mitochondrial respiration to this more oxidized state, as seen in the AD-N LCLs, is to slightly decrease ATP turnover (ATP-linked respiration) and slightly increase proton leak, likely through a small increase in UCP2 expression (although not confirmed) resulting in a slight decrease in reserve capacity. In contrast, as seen in the AD-A LCLs, a maladaptive response is to significantly increase proton leak (through increased UCP2 expression) as well as ATP turnover, maximal respiratory capacity and reserve capacity. When then exposed to a mild oxidative insult, both groups experience higher ATP demand and respond by increasing ATP turnover and proton leak respiration, thereby reducing reserve capacity; however, this response is greatly exaggerated in the maladaptive AD-A LCLs. We propose that while all cells are vulnerable to an ATP crisis and cell death under severe oxidative stress conditions, that in the maladaptive AD-A LCLs only a mild insult would be required to push the cells to a state of ATP crisis.CC BY · PubMed Central

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BackgroundInfluentialSelf-citation
PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production
Gómez-Escudero, J., Clemente, C., García-Weber, D., Acín‐Pérez, R., Millán, J., Enríquez, J. A., Bentley, K., Carmeliet, P., & Arroyo, A. G. (2019) · Scientific Reports · doi:10.1038/s41598-019-50866-x · Cited by 62
Bridging the Gap Between Physical Health and Autism Spectrum Disorder
Sala, R., Amet, L., Blagojevic-Stokic, N., Shattock, P., & Whiteley, P. (2020) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s251394 · Cited by 68
Mitochondria-containing extracellular vesicles from mouse vs. human brain endothelial cells for ischemic stroke therapy
Dave, K. M., Venna, V. R., Rao, K., Stolz, D. B., Brady, B. T., Quaicoe, V. A., Maniskas, M. E., Hildebrand, E. E., Green, D., Chen, M., et al. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.07.065 · Cited by 59
Early life metal exposure dysregulates cellular bioenergetics in children with regressive autism spectrum disorder
Frye, R. E., Cakir, J., Rose, S., Delhey, L. M., Bennuri, S. C., Tippett, M., Palmer, R. F., Austin, C. E., Curtin, P. C. P., & Arora, M. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00905-3 · Cited by 58
Self-citation
Cholic and deoxycholic acids induce mitochondrial dysfunction, impaired biogenesis and autophagic flux in skeletal muscle cells
Ábrigo, J., Olguín, H. C., Tacchi, F., Orozco-Aguilar, J., Valero‐Breton, M., Soto, J. A., Castro‐Sepúlveda, M., Elorza, Á. A., Simón, F., & Cabello‐Verrugio, C. (2023) · Biological Research · doi:10.1186/s40659-023-00436-3 · Cited by 59
5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats
Matsuo, K., Yabuki, Y., & Fukunaga, K. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.107975 · Cited by 53
Targeting mitochondrial metabolism for metastatic cancer therapy
Passaniti, A., Kim, M. S., Polster, B. M., & Shapiro, P. S. (2022) · Molecular Carcinogenesis · doi:10.1002/mc.23436 · Cited by 54
“mechanisms essential for these activities was the demonstration that the CADD522 compound inhibits mitochondrial respiration OCR(35) and maximum respiratory capacity.(83) Mitochondrial respiratory”
Background
The glutaminase inhibitor telaglenastat enhances the antitumor activity of signal transduction inhibitors everolimus and cabozantinib in models of renal cell carcinoma
Emberley, E. D., Pan, A., Chen, J., Dang, R., Gross, M. I., Huang, T. C., Li, W., MacKinnon, A. L., Singh, D., Sotirovska, N., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0259241 · Cited by 54
Modulation of Immunological Pathways in Autistic and Neurotypical Lymphoblastoid Cell Lines by the Enteric Microbiome Metabolite Propionic Acid
Frye, R. E., Nankova, B., Bhattacharyya, S., Rose, S., Bennuri, S. C., & MacFabe, D. F. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01670 · Cited by 51
Self-citation
Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome
Frye, R. E., Cox, D. M., Slattery, J. M., Tippett, M., Kahler, S. G., Granpeesheh, D., Damle, S., Legido, A., & Goldenthal, M. J. (2016) · Scientific Reports · doi:10.1038/srep19544 · Cited by 48
Self-citation
The Effect of Mitochondrial Supplements on Mitochondrial Activity in Children with Autism Spectrum Disorder
Delhey, L. M., Kilinc, E. N., Yin, L., Slattery, J. M., Tippett, M., Rose, S., Bennuri, S. C., Kahler, S. G., Damle, S., Legido, A., et al. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6020018 · Cited by 47
“Perhaps more unique is the fact that ETC activity in muscle [21,22], skin [23], buccal cells [11–13] and the brain [20] has been documented to be significantly increased, rather than decreased, in individuals with ASD, consistent with in vitro data showing elevated mitochondrial respiration in cell lines derived from…”
ResultSelf-citation
Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder
Pecorelli, A., Ferrara, F., Messano, N., Cordone, V., Schiavone, M. L., Cervellati, F., Woodby, B. L., Cervellati, C., Hayek, J., & Valacchi, G. (2020) · The FASEB Journal · doi:10.1096/fj.201902677r · Cited by 50
Increased Susceptibility to Ethylmercury-Induced Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines
Rose, S., Wynne, R. A., Frye, R. E., Melnyk, S., & James, S. J. (2015) · Journal of Toxicology · doi:10.1155/2015/573701 · Cited by 46
Self-citation
Mitochondrial morphology is associated with respiratory chain uncoupling in autism spectrum disorder
Frye, R. E., Lionnard, L., Singh, I. N., Karim, M. A., Chajra, H., Fréchet, M., Kissa, K., Racine, V., Ammanamanchi, A., McCarty, P. J., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01647-6 · Cited by 49
Self-citation
Mitochondrial Dysfunction and Its Relationship with mTOR Signaling and Oxidative Damage in Autism Spectrum Disorders
Yui, K., Sato, A., & Imataka, G. (2015) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557515666150324122930 · Cited by 41
“LCLs derived from children with ASD show decreased glutathione concentrations relative to oxidized disulfide glutathione as well as a decreased ratio of reduced nicotinamide adenine dinucleotide (NADH) to oxidized NAD and higher levels of 3-nitrotyrosine, a marker of protein oxidation that is indicative of chronic oxi…”
Background
Antipurinergic therapy for autism—An in-depth review
Naviaux, R. K. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.12.007 · Cited by 42
Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dysfunction
Burger, B. J., Rose, S., Bennuri, S. C., Gill, P. S., Tippett, M., Delhey, L. M., Melnyk, S., & Frye, R. E. (2017) · Frontiers in Pediatrics · doi:10.3389/fped.2017.00219 · Cited by 39
Self-citation
Mitochondria May Mediate Prenatal Environmental Influences in Autism Spectrum Disorder
Frye, R. E., Cakir, J., Rose, S., Palmer, R. F., Austin, C. E., Curtin, P. C. P., & Arora, M. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11030218 · Cited by 38
“To determine if these bioenergetics changes were specific to a subset of ASD LCLs, a cluster analysis was used to separated ASD LCLs into those with normal bioenergetics (AD-N) and those with atypical bioenergetics (AD-A) [109].”
BackgroundMethodSelf-citation
Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5
Oikawa, Y., Izumi, R., Koide, M., Hagiwara, Y., Kanzaki, M., Suzuki, N., Kikuchi, K., Matsuhashi, T., Akiyama, Y., Ichijo, M., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231064 · Cited by 36
“To clarify the mechanism of mitochondrial dysfunction in sIBM, we next examined the mitochondrial bioenergetic function governing the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using isolated myoblasts [11, 24, 25].”
Background
Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism
Oyarzábal, A., Bravo‐Alonso, I., Sánchez‐Aragó, M., Rejas, M. T., Merinero, B., García‐Cazorla, À., Artuch, R., Ugarte, M., & Rodríguez‐Pombo, P. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.01.016 · Cited by 36
Gut–brain axis in the executive function of austism spectrum disorder
Román, P., Rueda‐Ruzafa, L., Cardona, D., & Cortés‐Rodríguez, A. E. (2018) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000428 · Cited by 36
Mitochondrial Dysfunction Is Inducible in Lymphoblastoid Cell Lines From Children With Autism and May Involve the TORC1 Pathway
Bennuri, S. C., Rose, S., & Frye, R. E. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00269 · Cited by 33
“Since many environmental stressors may have their biological effect through increases in ROS (21, 44–46) and since ROS is elevated in many ASDderived tissues (45), including LCLs (37) and brain (47, 48), we hypothesized that prolonged environmental exposures, potentially through prolonged exposure to ROS, would alter…”
BackgroundResultInfluentialSelf-citation
Modulation of the Genome and Epigenome of Individuals Susceptible to Autism by Environmental Risk Factors
Koufaris, C., & Sismani, C. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16048699 · Cited by 35
“Recently published studies have reported that oxidative stress induces more prominent mitochondrial dysfunction in lymphoblastoid cells derived from subsets of ASD patients [47,48].”
Background
Assessment of oxidative stress in autism spectrum disorder using reactive oxygen metabolites and biological antioxidant potential
Morimoto, M., Hashimoto, T., Tsuda, Y., Nakatsu, T., Kitaoka, T., & Kyotani, S. (2020) · PLoS ONE · doi:10.1371/journal.pone.0233550 · Cited by 31
Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features
Yadav, S., Tiwari, V., Singh, M., Yadav, R. K., Roy, S., Devi, U., Gautam, S., Rawat, J. K., Ansari, M. N., Saeedan, A. S., et al. (2016) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-016-0532-2 · Cited by 34
“Pronounced oxidative stress with change in membrane permeability and associated mitochondrial dysfunction are few of the players toward the pathogenesis of autism disorders [14, 44].”
Background
Bioenergetic variation is related to autism symptomatology
Delhey, L. M., Kilinc, E. N., Yin, L., Slattery, J. M., Tippett, M., Wynne, R. A., Rose, S., Kahler, S. G., Damle, S., Legido, A., et al. (2017) · Metabolic Brain Disease · doi:10.1007/s11011-017-0087-0 · Cited by 32
“Indeed, we have repeatedly demonstrated in the laboratory that a subset of lymphoblastoid cell lines derived from children with ASD have respiratory rates approximately twice that of control cell lines (Rose et al. 2014a, b, 2015a, b; Frye et al. 2016c, 2017a; Rose et al. 2017).”
BackgroundResultInfluentialSelf-citation
Variations in Mitochondrial Respiration Differ in IL-1ß/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders
Jyonouchi, H., Geng, L., Rose, S., Bennuri, S. C., & Frye, R. E. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00071 · Cited by 34
“, North Billerica, MA, United States) was used for measurement of oxygen consumption ratio (OCR), which is an indicator of mitochondrial respiration, in real time in live PBMCs (14, 27).”
MethodSelf-citation
Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes
Peper, J., Kownatzki-Danger, D., Weninger, G., Seibertz, F., Pronto, J. R. D., Sutanto, H., Pacheu‐Grau, D., Hindmarsh, R., Brandenburg, S., Kohl, T., et al. (2021) · Circulation Research · doi:10.1161/circresaha.119.316547 · Cited by 30
Developmental Block and Programmed Cell Death in Bos indicus Embryos: Effects of Protein Supplementation Source and Developmental Kinetics
Garcia, S. M., Marinho, L. S. R., Lunardelli, P. A., Seneda, M. M., & Meirelles, F. V. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119463 · Cited by 29
“In addition to differing numbers of antral follicles, zebu and taurine cows diverge in several aspects, such as estrus manifestation [33], progesterone concentration, follicle size [34] and IGF-I and insulin concentrations [35].”
Background
NEK10 interactome and depletion reveal new roles in mitochondria
de Oliveira, A. P., Basei, F. L., Slepicka, P. F., Ferezin, C. D. C., Melo‐Hanchuk, T. D., de Souza, E. E., de Lima, T. I., dos Santos, V. T., Mendes, D., Silveira, L. R., et al. (2020) · Proteome Science · doi:10.1186/s12953-020-00160-w · Cited by 30
“of experimental oxygen consumption rate (OCR) data type nomenclature, adapted from Rose and coworkers [56].”
Induction of a Senescence-Like Phenotype in Cultured Human Fetal Microglia During HIV-1 Infection
Chen, N. C., Partridge, A. T., Tüzer, F., Cohen, J., Nacarelli, T., Navas, S., Sell, C., Torres, C. A., & Martín‐García, J. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly022 · Cited by 32
Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes
Shaw, G. A., Hyer, M. M., Targett, I. L., Dyer, S. K., Turkson, S., Burns, C. M., & Neigh, G. N. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.021 · Cited by 28
Passaging capability of human corneal endothelial cells derived from old donors with and without accelerating cell attachment
Parekh, M., Peh, G. S. L., Mehta, J. S., Ramos, T., Ponzin, D., Ahmad, S., & Ferrari, S. (2019) · Experimental Eye Research · doi:10.1016/j.exer.2019.107814 · Cited by 28
A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance
Mertens, R. T., Misra, A., Xiao, P., Baek, S., Rone, J. M., Mangani, D., Sivanathan, K. N., Arojojoye, A. S., Awuah, S. G., Lee, I., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.06.001 · Cited by 27
Therapeutic potential of stilbenes in neuropsychiatric and neurological disorders: A comprehensive review of preclinical and clinical evidence
Socała, K., Żmudzka, E., Lustyk, K., Zagaja, M. P., Brighenti, V., Costa, A., Andres‐Mach, M., Pytka, K., Martinelli, I., Mandrioli, J., et al. (2024) · Phytotherapy Research · doi:10.1002/ptr.8101 · Cited by 29
Repurposing the Electron Transfer Reactant Phenazine Methosulfate (PMS) for the Apoptotic Elimination of Malignant Melanoma Cells through Induction of Lethal Oxidative and Mitochondriotoxic Stress
Hua, A., Justiniano, R., Perer, J., Park, S., Li, H., Cabello, C. M., & Wondrak, G. T. (2019) · Cancers · doi:10.3390/cancers11050590 · Cited by 26
“A Seahorse Extracellular Flux (XF) 96 Analyzer (Seahorse Bioscience, Inc, North Billerica, MA, USA) using a specialized oxygen consumption rate (OCR) kit (Seahorse XFe96 FluxPaksTM, Agilent, Santa Clara, CA, USA) was employed in 96 well format according to the manufacturer’s specifications measuring OCR as a quantitat…”
Method
Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art
Aschner, M., Martins, A. C., Oliveira‐Paula, G. H., Skalny, A. V., Zaitseva, I. P., Bowman, A. B., Kirichuk, A. A., Santamarı́a, A., Tizabi, Y., & Tinkov, A. A. (2024) · Current Research in Toxicology · doi:10.1016/j.crtox.2024.100170 · Cited by 26
“In this regard, lymphoblastoid cell lines derived from patients with ASD were more susceptible to oxidative stress and had significant physiological abnormalities in mitochondrial function (Rose et al., 2014).”
Background
Oxidative Stress Challenge Uncovers Trichloroacetaldehyde Hydrate-Induced Mitoplasticity in Autistic and Control Lymphoblastoid Cell Lines
Frye, R. E., Rose, S., Wynne, R. A., Bennuri, S. C., Blossom, S. J., Gilbert, K. M., Heilbrun, L. P., & Palmer, R. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-04821-3 · Cited by 25
Self-citation
The Effect of Freeze-Thaw Cycles on Gene Expression Levels in Lymphoblastoid Cell Lines
Çalışkan, M., Pritchard, J. K., Ober, C., & Gilad, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107166 · Cited by 24
“Thousands of published studies have used LCLs to address a wide range of questions in human biology, including studies of gene regulatory mechanisms [3,4,6–14], drug toxicity [15,16], response to stress [17,18], and case control studies of human diseases [19,20].”
Background
Serum microRNAs in ASD: Association With Monocyte Cytokine Profiles and Mitochondrial Respiration
Jyonouchi, H., Geng, L., Törüner, G., Rose, S., Bennuri, S. C., & Frye, R. E. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00614 · Cited by 27
“Samples were sent to Dr. R. Frye’s laboratory on dry ice where the Seahorse Extracellular Flux (XF) 96 Analyzer (Seahorse Bioscience, Inc., North Billerica, MA, USA) was used to measure oxygen consumption ratio (OCR; pMol/min), which is an indicator of mitochondrial respiration, in real time in live PBMCs. ATP-linked…”
MethodInfluentialSelf-citation
Targeting breast cancer metabolism with a novel inhibitor of mitochondrial ATP synthesis
Kim, M. S., Gernapudi, R., Cedeno, Y. C., Polster, B. M., Martinez, R., Shapiro, P., Kesari, S., Nurmemmedov, E., & Passaniti, A. (2020) · Oncotarget · doi:10.18632/oncotarget.27743 · Cited by 22
“Baseline cellular OCR (BL) was calculated from basal respiration after subtracting NM [111].”
Method
Physiological mediators of prenatal environmental influences in autism spectrum disorder
Frye, R. E., Cakir, J., Rose, S., Palmer, R. F., Austin, C. E., & Curtin, P. C. P. (2021) · BioEssays · doi:10.1002/bies.202000307 · Cited by 24
“dysregulation of oxidative stress at the inner mitochondria membrane in neurodevelopmental disorders,[15] including ASD[78] and Fragile X,[79] as manifested by proton leak across the inner mitochondrial membrane.”
BackgroundSelf-citation
IKCa channels control breast cancer metabolism including AMPK-driven autophagy
Gross, D., Bischof, H., Maier, S., Sporbeck, K., Birkenfeld, A. L., Malli, R., Ruth, P., Proikas‐Cezanne, T., & Łukowski, R. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05329-z · Cited by 23
Serum starvation affects mitochondrial metabolism of adipose-derived stem/stromal cells
Giannasi, C., Niada, S., Morte, E. D., Casati, S. R., Palma, C. D., & Brini, A. T. (2023) · Cytotherapy · doi:10.1016/j.jcyt.2023.03.004 · Cited by 21
Enteric ecosystem disruption in autism spectrum disorder: Can the microbiota and macrobiota be restored?
Slattery, J., MacFabe, D., Kahler, S., & Frye, R. (2016) · Current Pharmaceutical Design · doi:10.2174/1381612822666160905123953 · Cited by 20
Self-citation
Inheritance of HLA-Cw7 Associated With Autism Spectrum Disorder (ASD)
Harville, T., Rhodes-Clark, B. S., Bennuri, S. C., Delhey, L. M., Slattery, J. M., Tippett, M., Wynne, R. A., Rose, S., Kahler, S. G., & Frye, R. E. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00612 · Cited by 20
Self-citation
Human neurotropic polyomavirus, JC virus, agnoprotein targets mitochondrion and modulates its functions
Saxena, R., Saribas, S., Jadiya, P., Tomar, D., Kaminski, R., Elrod, J. W., & Safak, M. (2020) · Virology · doi:10.1016/j.virol.2020.11.004 · Cited by 18
“That is, this inhibitor provides information about the levels of O2 consumption, directly coupled to ATP production (Supplement 1) (Rose et al., 2014).”
Background
Enhancing enterocyte fatty acid oxidation in mice affects glycemic control depending on dietary fat
Ramachandran, D., Clara, R., Fedele, S., Michel, L., Burkard, J., Kaufman, S., Alvarado-Diaz, A., Weissfeld, N., Bock, K. D., Prip‐Buus, C., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-29139-6 · Cited by 18
Generation and Characterisation of Mice Deficient in the Multi-GTPase Domain Containing Protein, GIMAP8
Webb, L. M. C., Pascall, J. C., Hepburn, L., Carter, C., Turner, M., & Butcher, G. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110294 · Cited by 17
“We used the Seahorse Extracellular Flux (XF) 96 Analyzer (Seahorse Bioscience, Inc, North Billerica, MA, USA), to measure the oxygen consumption rate (OCR), an indicator of mitochondrial respiration, in real-time in live intact B lymphocytes as previously described [51].”
Method
Nitrosative Stress in Autism: Supportive Evidence and Implications for Mitochondrial Dysfunction
Frye, R. E., Rose, S., Voinsky, I., & Gurwitz, D. (2024) · Advanced Science · doi:10.1002/advs.202304439 · Cited by 16
Self-citation
Mitochondrial metabolism assessment of lycaon-dog fetuses in interspecies somatic cell nuclear transfer
Son, Y., Jeong, Y. I., Hwang, K. C., Jeong, Y. I., & Hwang, W. S. (2021) · Theriogenology · doi:10.1016/j.theriogenology.2021.01.010 · Cited by 15
In Vivo Detection of Mitochondrial Dysfunction Induced by Clinical Drugs and Disease-Associated Genes Using a Novel Dye ZMJ214 in Zebrafish
Sasagawa, S., Nishimura, Y., Koiwa, J., Nomoto, T., Shintou, T., Murakami, S., Yuge, M., Kawaguchi, K., Kawase, R., Miyazaki, T., et al. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00751 · Cited by 15
Paclitaxel Inhibits KCNQ Channels in Primary Sensory Neurons to Initiate the Development of Painful Peripheral Neuropathy
Wu, Z., Törő, G., Xu, G., Dang, D., Prater, C., & Yang, Q. (2022) · Cells · doi:10.3390/cells11244067 · Cited by 14
Oxidative stress and neuroimmune proteins in a mouse model of autism
Uddin, M. N., Mondal, T. K., Yao, Y., MANLEY, K. M., & Lawrence, D. A. (2023) · Cell Stress and Chaperones · doi:10.1007/s12192-023-01331-2 · Cited by 17
Bioenergetic signatures of neurodevelopmental regression
Frye, R. E., McCarty, P. J., Werner, B. A., Rose, S., & Scheck, A. C. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1306038 · Cited by 15
Self-citation
Examining Hemin and its Derivatives: Induction of Heme-Oxygenase-1 Activity and Oxidative Stress in Breast Cancer Cells through Collaborative Experimental Analysis and Molecular Dynamics Simulations
Alsharabasy, A. M., Lagarias, P. I., Papavasileiou, K. D., Afantitis, A., Farràs, P., Glynn, S. A., & Pandit, A. S. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00989 · Cited by 14
Role of zinc transporter ZIP12 in susceptibility‐weighted brain magnetic resonance imaging (MRI) phenotypes and mitochondrial function
Strong, M. D., Hart, M. D., Tang, T. Z., Ojo, B. A., Wu, L., Nacke, M. R., Agidew, W. T., Hwang, H. J., Hoyt, P. R., Bettaieb, A., et al. (2020) · The FASEB Journal · doi:10.1096/fj.202000772r · Cited by 14
Evaluation of therapeutic effect of Premna herbacea in diabetic rat and isoverbascoside against insulin resistance in L6 muscle cells through bioenergetics and stimulation of JNK and AKT/mTOR signaling cascade
Kashyap, B., Barge, S., Bharadwaj, S., Deka, B., Rahman, S., Ghosh, A., Manna, P., Dutta, P. P., Sheikh, Y., Kandimalla, R., et al. (2021) · Phytomedicine · doi:10.1016/j.phymed.2021.153761 · Cited by 14
Association of NGF and Mitochondrial Respiration with Autism Spectrum Disorder
Gevezova, M., Minchev, D. S., Pacheva, I., Todorova, T., Yordanova, R. V., Timova, E., Ivanov, I. S., & Sarafian, V. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911917 · Cited by 15
“Furthermore, we found that reserve respiratory capacity is almost 40% higher in ASD children with developmental regression compared to those without, which is regarded by some authors as a protective adaptation in response to environmental stressors [83].”
Background
Verbascoside as a potential SGLT2 inhibitor in diabetic nephropathy: Targeting AMPK activation to suppress NOX4/NF-κB signaling and attenuate inflammation and fibrosis
Ahmed, S. A., Saikia, K., Basumatary, D., Gurumayum, S., Swargiary, D., & Borah, J. C. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114825 · Cited by 13
Brassinosteroids Control the Inflammation, Oxidative Stress and Cell Migration Through the Control of Mitochondrial Function on Skin Regeneration
Xiong, J., Bonney, S., Gonçalves, R. V., & Esposito, D. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120887 · Cited by 12
Bridging cell-scale simulations and radiologic images to explain short-time intratumoral oxygen fluctuations
Kingsley, J., Costello, J. R., Raghunand, N., & Rejniak, K. A. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009206 · Cited by 12
“, 1–350 amol/s per cell[29], and 1–120 amol/s per cell[30]), changes reported in the same cells varied no more than 10-fold when the culture conditions were modified[14,31].”
Background
Redox System Dysfunction as a Key Mechanism in Autism Spectrum Disorder Pathogenesis
de Oliveira, C. A., Iorio, E. L., & Espíndola, F. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26209850 · Cited by 12
Enhancing oxidative phosphorylation over glycolysis for energy production in cultured mesenchymal stem cells
Monsour, M., Gorsky, A., Nguyen, H., Castelli, V., Lee, J.-Y., & Borlongan, C. V. (2022) · Neuroreport · doi:10.1097/wnr.0000000000001828 · Cited by 12

Authors: Rose, S., Frye, R. E., Slattery, J., Wynne, R., Tippett, M., Pavliv, O., Melnyk, S., & James, S. J.
Affiliations: Arkansas Children's Hospital (US)
Corresponding author: Frye, Richard E.
ORCID: Rose, Shannon
Frye, Richard E.
Slattery, John
Pavliv, Oleksandra
Melnyk, Stepan
James, S. Jill
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2014-01-08
Volume: 9
Issue: 1
Pages: e85436
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0085436
PMC: PMC3885720
OpenAlex: W2163485668
Cited by: 168
References: 61
Citations by year: 2026: 9 · 2025: 9 · 2024: 20 · 2023: 7 · 2022: 22 · 2021: 17 · 2020: 18 · 2019: 9 · 2018: 10 · 2017: 12 · 2016: 13 · 2015: 16 · 2014: 6
FWCI: 6.42
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: PLoS ONE (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Arkansas Biosciences Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords: autism spectrum disorder, mitochondrial dysfunction, oxidative stress, reserve capacity, lymphoblastoid cell lines, reactive oxygen species, UCP2, glycolysis, ATP-linked respiration, mitochondrial heterogeneity
MeSH terms: Uncoupling Protein 2, Autistic Disorder, Cell Line, Child, Child, Preschool, Female, Glycolysis, Humans, Ion Channels, Lymphocytes, Male, Mitochondria, Naphthoquinones, Oxidation-Reduction, Protons, Case-Control Studies, Reactive Oxygen Species, Oxidative Stress, Cell Respiration, Mitochondrial Proteins, Mitochondrial Membranes

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Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort

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