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

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.

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