Phoenix Children's Hospital, Phoenix, AZ, USA.
University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA.
Transl Psychiatry. 2021 Oct 13;11(1):527. doi: 10.1038/s41398-021-01647-6.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.
自闭症谱系障碍 (ASD) 是一种神经发育障碍，与线粒体代谢的独特变化有关，包括呼吸率升高和形态改变。我们研究了 18 名 ASD 儿童来源的成纤维细胞中的电子传递链 (ETC) 复合物活性，以及 ASD 参与者和 4 名典型发育对照者来源的成纤维细胞中的线粒体形态测量。在 ASD 参与者中，症状严重程度通过社会反应量表和异常行为检查表进行测量。混合模型回归表明，线粒体形态的改变与 ETC 复合物 I+III 和 IV 活性以及 ETC 复合物 I+III 和 IV 活性之间的差异有关。ETC 复合物 IV 活性相对升高的 ASD 参与者亚组表现出更典型的线粒体形态和更轻微的 ASD 相关症状。鉴于从儿童获取成纤维细胞的侵入性，本研究受到样本量的限制。此外，由于线粒体功能在组织间存在异质性，因此结果可能特定于成纤维细胞呼吸。先前的研究分别描述了 ASD 儿童来源的细胞中 ETC 复合物 IV 活性升高和线粒体形态变化，但这是第一项将线粒体代谢中的这两种发现联系起来的研究。ETC 复合物 I+III 和 IV 活性差异与正常形态之间的关联表明，ASD 个体中的线粒体可能需要 ETC 解偶联才能最佳发挥功能。应进一步研究评估这些独特代谢变化背后的分子机制。试验注册：本研究中使用的方案在 clinicaltrials.gov 中注册为 NCT02000284 和 NCT02003170。
