Mitochondrial Dysfunction Is Inducible in Lymphoblastoid Cell Lines From Children With Autism and May Involve the TORC1 Pathway
AffiliationUniv Arizona, Coll Med Phoenix, Dept Child Hlth
KeywordsPsychiatry and Mental health
mechanistic target of rapamycin
reactive oxygen species
MetadataShow full item record
PublisherFRONTIERS MEDIA SA
CitationBennuri SC, Rose S and Frye RE (2019) Mitochondrial Dysfunction Is Inducible in Lymphoblastoid Cell Lines From Children With Autism and May Involve the TORC1 Pathway. Front. Psychiatry 10:269. doi: 10.3389/fpsyt.2019.00269
JournalFRONTIERS IN PSYCHIATRY
RightsCopyright © 2019 Bennuri, Rose and Frye. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractWe previously developed a lymphoblastoid cell line (LCL) model of mitochondrial dysfunction in autism spectrum disorder (ASD); some individuals with ASD showed mitochondrial dysfunction (AD-A) while other individuals (AD-N) demonstrated mitochondrial respiration similar to controls (CNT). To test the hypothesis that mitochondrial dysfunction could be a consequence of environmental exposures through chronic elevations in reactive oxygen species (ROS), we exposed LCLs to prolonged ROS. We also examined expression of metabolic regulatory genes and the modulating effect of the mechanistic target of rapamycin (mTOR) pathway. Prolonged ROS exposure induced or worsened mitochondrial dysfunction in all LCL groups. Expression of genes associated with ROS protection was elevated in both AD-N and AD-A LCLs, but mitochondrial fission/fusion and mitoplasticity gene expression was only increased in AD-N LCLs. Partial least squares discriminant analysis showed that mTOR, UCP2 (uncoupling protein 2), SIRT1 (sirtuin 1), and MFN2 (mitofusin-2) gene expression differentiated LCL groups. Low-dose rapamycin (0.1 nM) normalized respiration with the magnitude of this normalization greater for AD-A LCLs, suggesting that the mammalian target of rapamycin complex 1 (mTORC1) pathway may have a different dynamic range for regulating mitochondrial activity in individuals with ASD with and without mitochondrial dysfunction, potentially related to S6K1 (S6 kinase beta-1) regulation. Understanding pathways that underlie mitochondrial dysfunction in ASD may lead to novel treatments.
NoteOpen access journal
VersionFinal published version
SponsorsArkansas Biosciences Institute (Little Rock, AR); Jonty Foundation (St. Paul, MN); Autism Research Institute (San Diego, CA); Gupta Family Foundation (Atherton, CA); Jane Botsford Johnson Foundation (New York, NY); Jager Family Foundation (Chicago, IL); Phoenix Children's Hospital Foundation (Phoenix, AZ)