Trisomy 21 results in modest impacts on mitochondrial function and central carbon metabolism.
Trisomy 21 results in modest impacts on mitochondrial function and central carbon metabolism.
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三体21导致对线粒体功能和中心碳代谢的适度影响。
DOI：
10.1016/j.freeradbiomed.2021.06.003
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发表时间：
2021-08-20
影响因子：
7.4
通讯作者：
Roede JR
中科院分区：
文献类型：
--
作者：
Anderson CC;Marentette JO;Prutton KM;Rauniyar AK;Reisz JA;D'Alessandro A;Maclean KN;Saba LM;Roede JR
唐氏综合征（DS）是智力残疾最常见的遗传原因。从机制上讲，氧化应激和线粒体功能障碍被报告为许多DS相关合并症的病因学因素，并且先前已在许多DS体外和体内模型中报告。本研究的目的是测试通过皮肤活检从DS个体获得的成纤维细胞中线粒体功能障碍的存在，并评估21三体对中心碳代谢的影响。使用细胞外流量测定匹配的真皮成纤维细胞从整倍体和DS个人，我们发现，基础线粒体功能障碍是相当温和的。与整倍体对照相比，用线粒体应激物的混合物应激细胞揭示了DS细胞中的显著线粒体缺陷。细胞外酸化率的评估没有发现糖酵解的基线异常;然而，利用同位素标记的葡萄糖和谷氨酰胺进行的代谢组学评估显示DS细胞的中心碳代谢改变。具体来说，我们观察到更大的葡萄糖依赖性，摄取和流量到氧化阶段的戊糖磷酸途径在DS成纤维细胞。此外，使用诱导多能干细胞（iPSC），我们发现DS iPSC中的线粒体功能与先前发表的使用胎儿细胞的研究相似。总之，这些数据表明，异常的中央碳代谢是一个候选机制，应激相关的线粒体功能障碍的DS。
Down syndrome (DS) is the most common genetic cause of intellectual disability. Mechanistically, oxidative stress and mitochondrial dysfunction are reported to be etiological factors for many of the DS-related comorbidities and have previously been reported in a number of in vitro and in vivo models of DS. The purpose of this study was to test for the presence of mitochondrial dysfunction in fibroblast cells obtained via skin biopsy from individuals with DS, and to assess the impact of trisomy 21 on central carbon metabolism. Using extracellular flux assays in matched dermal fibroblasts from euploid and DS individuals, we found that basal mitochondrial dysfunction is quite mild. Stressing the cells with a cocktail of mitochondrial stressors revealed a significant mitochondrial deficit in DS cells compared to euploid controls. Evaluation of extracellular acidification rate did not reveal a baseline abnormality in glycolysis; however, metabolomic assessments utilizing isotopically labeled glucose and glutamine revealed altered central carbon metabolism in DS cells. Specifically, we observed greater glucose dependency, uptake and flux into the oxidative phase of the pentose phosphate pathway in DS fibroblasts. Furthermore, using induced pluripotent stem cells (iPSC) we found that mitochondrial function in DS iPSCs was similar to the previously published studies employing fetal cells. Together, these data indicate that aberrant central carbon metabolism is a candidate mechanism for stress-related mitochondrial dysfunction in DS.
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