Frye Richard E, McCarty Patrick J, Werner Brianna A, Rose Shannon, Scheck Adrienne C
Autism Discovery and Treatment Foundation, Phoenix, AZ, United States.
Tulane University School of Medicine, New Orleans, LA, United States.
Front Physiol. 2024 Feb 19;15:1306038. doi: 10.3389/fphys.2024.1306038. eCollection 2024.
Studies have linked autism spectrum disorder (ASD) to physiological abnormalities including mitochondrial dysfunction. Mitochondrial dysfunction may be linked to a subset of children with ASD who have neurodevelopmental regression (NDR). We have developed a cell model of ASD which demonstrates a unique mitochondrial profile with mitochondrial respiration higher than normal and sensitive to physiological stress. We have previously shown similar mitochondrial profiles in individuals with ASD and NDR. Twenty-six ASD individuals without a history of NDR (ASD-NoNDR) and 15 ASD individuals with a history of NDR (ASD-NDR) were recruited from 34 families. From these families, 30 mothers, 17 fathers and 5 typically developing (TD) siblings participated. Mitochondrial respiration was measured in peripheral blood mononuclear cells (PBMCs) with the Seahorse 96 XF Analyzer. PBMCs were exposed to various levels of physiological stress for 1 h prior to the assay using 2,3-dimethoxy-1,4-napthoquinone. ASD-NDR children were found to have higher respiratory rates with mitochondria that were more sensitive to physiological stress as compared to ASD-NoNDR children, similar to our cellular model of NDR. Differences in mitochondrial respiration between ASD-NDR and TD siblings were similar to the differences between ASD-NDR and ASD-NoNDR children. Interesting, parents of children with ASD and NDR demonstrated patterns of mitochondrial respiration similar to their children such that parents of children with ASD and NDR demonstrated elevated respiratory rates with mitochondria that were more sensitive to physiological stress. In addition, sex differences were seen in ASD children and parents. Age effects in parents suggested that mitochondria of older parents were more sensitive to physiological stress. This study provides further evidence that children with ASD and NDR may have a unique type of mitochondrial physiology that may make them susceptible to physiological stressors. Identifying these children early in life before NDR occurs and providing treatment to protect mitochondrial physiology may protect children from experiencing NDR. The fact that parents also demonstrate mitochondrial respiration patterns similar to their children implies that this unique change in mitochondrial physiology may be a heritable factor (genetic or epigenetic), a result of shared environment, or both.
研究已将自闭症谱系障碍（ASD）与包括线粒体功能障碍在内的生理异常联系起来。线粒体功能障碍可能与一部分患有神经发育倒退（NDR）的自闭症儿童有关。我们开发了一种自闭症细胞模型，该模型显示出独特的线粒体特征，其线粒体呼吸高于正常水平且对生理应激敏感。我们之前在患有自闭症和神经发育倒退的个体中也发现了类似的线粒体特征。从34个家庭中招募了26名无神经发育倒退病史的自闭症个体（ASD-无NDR）和15名有神经发育倒退病史的自闭症个体（ASD-NDR）。在这些家庭中，30名母亲、17名父亲和5名发育正常（TD）的兄弟姐妹参与了研究。使用海马96 XF分析仪测量外周血单个核细胞（PBMC）中的线粒体呼吸。在测定前，使用2,3-二甲氧基-1,4-萘醌使PBMC暴露于不同水平的生理应激1小时。与ASD-无NDR儿童相比，发现ASD-NDR儿童的呼吸速率更高，其线粒体对生理应激更敏感，这与我们的神经发育倒退细胞模型相似。ASD-NDR儿童与发育正常的兄弟姐妹之间线粒体呼吸的差异与ASD-NDR儿童和ASD-无NDR儿童之间的差异相似。有趣的是，患有自闭症和神经发育倒退儿童的父母表现出与他们孩子相似的线粒体呼吸模式，即患有自闭症和神经发育倒退儿童的父母表现出较高的呼吸速率，其线粒体对生理应激更敏感。此外，在自闭症儿童及其父母中观察到了性别差异。父母的年龄效应表明，年龄较大的父母的线粒体对生理应激更敏感。这项研究提供了进一步的证据，表明患有自闭症和神经发育倒退的儿童可能具有一种独特类型的线粒体生理学，这可能使他们易受生理应激源的影响。在神经发育倒退发生之前尽早识别这些儿童并提供保护线粒体生理学的治疗，可能会保护儿童不经历神经发育倒退。父母也表现出与他们孩子相似的线粒体呼吸模式这一事实意味着，线粒体生理学的这种独特变化可能是一种可遗传因素（遗传或表观遗传）、共同环境的结果，或两者兼而有之。
