Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines

S Rose,S J James,R Wynne,S Melnyk,J Slattery,M Tippett,R E Frye

doi:10.1038/tp.2014.15

Abstract

There is an increasing recognition that mitochondrial dysfunction is associated with autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction and how mitochondrial abnormalities might interact with other physiological disturbances such as oxidative stress. Reserve capacity is a measure of the ability of the mitochondria to respond to physiological stress. In this study, we demonstrate, for the first time, that lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) have an abnormal mitochondrial reserve capacity before and after exposure to reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited abnormally high reserve capacity at baseline and a sharp depletion of reserve capacity when challenged with ROS. This depletion of reserve capacity was found to be directly related to an atypical simultaneous increase in both proton-leak respiration and adenosine triphosphate-linked respiration in response to increased ROS in this AD LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with N-acetylcysteine, a glutathione precursor, prevented these abnormalities and improved glutathione metabolism, suggesting a role for altered glutathione metabolism associated with this type of mitochondrial dysfunction. The results of this study suggest that a significant subgroup of AD children may have alterations in mitochondrial function, which could render them more vulnerable to a pro-oxidant microenvironment as well as intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxins. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.

Highlights

The autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders defined by impairments in communication and social interaction along with restrictive and repetitive behaviors.1 An estimated 1 out of 88 individuals in the United States are currently affected with an ASD and the incidence continues to rise.2Mitochondrial dysfunction has become increasingly recognized as a major physiological disturbance in ASD.3 the etiology of mitochondrial dysfunction is not known
We examined mitochondrial respiratory activity in lymphoblastoid cell lines (LCLs) derived from autistic disorder (AD) children and unaffected control individuals
As AD and control LCLs differed markedly in the changes in Adenosine-5'-triphosphate-Linked Respiration (ALR) and proton-leak respiration (PLR) with DMNQ challenge, we examined whether the Mitochondrial function in AD LCLs with reactive oxygen species (ROS) challenge changes in these respiratory parameters could differentiate AD LCL subgroups

Summary

Introduction

The autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders defined by impairments in communication and social interaction along with restrictive and repetitive behaviors. An estimated 1 out of 88 individuals in the United States are currently affected with an ASD and the incidence continues to rise.2Mitochondrial dysfunction has become increasingly recognized as a major physiological disturbance in ASD. the etiology of mitochondrial dysfunction is not known. An estimated 1 out of 88 individuals in the United States are currently affected with an ASD and the incidence continues to rise.. Mitochondrial dysfunction has become increasingly recognized as a major physiological disturbance in ASD.. The etiology of mitochondrial dysfunction is not known. Mitochondrial deoxyribonucleic acid mutations are commonly found in classical mitochondrial disease (MD), such mutations are only found in 23% of ASD children diagnosed with MD.. Mitochondrial deoxyribonucleic acid mutations are commonly found in classical mitochondrial disease (MD), such mutations are only found in 23% of ASD children diagnosed with MD.3 This raises the possibility of acquired mitochondrial dysfunction as mitochondrial damage can result from environmental exposures implicated in ASD such as heavy metals, exhaust fumes, polychlorinated biphenyls or pesticides. Mitochondrial deoxyribonucleic acid mutations are commonly found in classical mitochondrial disease (MD), such mutations are only found in 23% of ASD children diagnosed with MD. This raises the possibility of acquired mitochondrial dysfunction as mitochondrial damage can result from environmental exposures implicated in ASD such as heavy metals, exhaust fumes, polychlorinated biphenyls or pesticides.

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