Mitochondrial Dysfunction Is Inducible in Lymphoblastoid Cell Lines From Children With Autism and May Involve the TORC1 Pathway.

Richard E Frye,Sirish C Bennuri,Shannon Rose

doi:10.3389/fpsyt.2019.00269

Abstract

We 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.

Highlights

Mitochondria are involved in many essential cellular functions; besides production of adenosine triphosphate (ATP), mitochondria are essential for calcium buffering, redox regulation, apoptosis, and inflammation
autism spectrum disorder (ASD) lymphoblastoid cell line (LCL) with atypical mitochondrial respiration, called ASD showed mitochondrial dysfunction (AD-A) LCLs, developed atypical mitochondrial respiration as an adaptation to previous environmental exposures, potentially through prolonged exposure to reactive oxygen species (ROS) since oxidative stress is a common mechanism in which environmental agents perturb cellular physiology
We conducted three experiments: 1) we examined the effect of prolonged exposure to ROS on mitochondrial respiration; 2) we examined differences in the expression of genes important for mitochondrial respiration, those involved in allowing the mitochondria to adapt to adverse physiological conditions, across different clinical types (ASD vs. typical developing) and physiological types; and 3) we examined the effect of low-dose rapamycin on mitochondrial function, to determine whether a specific regulatory pathway (S6K1) may be involved in maintaining atypical mitochondrial function in the autistic disorder (AD)-A LCLs

Summary

Introduction

Mitochondria are involved in many essential cellular functions; besides production of adenosine triphosphate (ATP), mitochondria are essential for calcium buffering, redox regulation, apoptosis, and inflammation. Metabolic Abnormalities in Autism neurodevelopmental disorders, autism spectrum disorder (ASD) [10, 11] and genetic syndromes closely associated with ASD including mechanistic target of rapamycin (mTOR) [12,13,14,15]; phosphatase and tensin homolog (PTEN) [16] and WDR45 [17] mutations; Rett [18,19,20], Phelan–McDermid [21], Angelman [22], and Down [23, 24] syndromes; as well as 15q11q13 duplication [25, 26] and septo-optic dysplasia [27]. Unlike classic mitochondrial disease, where mitochondrial activity is depressed, electron transport chain (ETC) activity in individuals with ASD has been reported to be elevated significantly above normal in muscle [28, 29], skin [30], gut mucosa [31], buccal epithelium [32,33,34], and brain [35]

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