Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort
Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort
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DOI：
10.1371/journal.pone.0085436
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发表时间：
2014-01-08
期刊：
影响因子：
3.7
通讯作者：
James, S. Jill
中科院分区：
文献类型：
--
作者：
Rose, Shannon;Frye, Richard E.;James, S. Jill
越来越多的人认识到线粒体功能障碍与自闭症谱系障碍有关。然而，很少有人关注线粒体功能障碍的病因，或者线粒体异常如何与其他与自闭症相关的生理障碍（如氧化应激）相互作用。在当前的研究中，我们使用呼吸测量法来检测来自自闭症儿童的淋巴母细胞样细胞系（LCLs）以及年龄和性别匹配的对照LCLs的储备能力，这是一种衡量线粒体对生理应激反应能力的指标。我们首次证明，来自AD儿童的LCLs在暴露于越来越高浓度的2,3-二甲氧基-1,4-萘醌（DMNQ）之前和之后具有异常的线粒体储备能力，DMNQ是一种增加细胞内活性氧（ROS）的药物。具体而言，与对照lcl相比，AD lcl在基线时表现出更高的储备容量，当ROS暴露增加时，储备容量的消耗会更急剧。详细的研究表明，AD LCLs中所见的储备能力异常是由于基线时atp相关呼吸和最大呼吸能力较高，同时随着ROS的增加，质子泄漏呼吸显著增加。我们进一步证明，这些储备容量异常是由25个AD lcl中的8个（32%）亚群驱动的。对储备能力异常的AD LCLs亚群的进一步研究表明，它更依赖于糖酵解和解偶联蛋白2来调节线粒体内膜的氧化应激。这项研究表明，AD儿童的一个重要亚群可能存在线粒体功能的改变，这可能使他们更容易受到由内在和外在ROS来源（如免疫激活和促氧化环境毒物）引起的促氧化微环境的影响。这些发现与阿尔茨海默病是由遗传和环境因素共同引起的观点是一致的。
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.