Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: Altered mitochondrial and energy metabolism.
Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: Altered mitochondrial and energy metabolism.
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DOI：
10.1016/j.stemcr.2021.04.022
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发表时间：
2021-06-08
影响因子：
5.9
通讯作者：
Meyer M
中科院分区：
文献类型：
--
作者：
Okarmus J;Havelund JF;Ryding M;Schmidt SI;Bogetofte H;Heon-Roberts R;Wade-Martins R;Cowley SA;Ryan BJ;Færgeman NJ;Hyttel P;Meyer M
PARK2 （parkin）突变导致早发性帕金森病（PD）。Parkin是一种泛素E3连接酶，参与多种细胞功能，包括线粒体稳态。然而，由帕金耗竭引起的具体代谢组学变化尚不清楚。在这里，我们使用具有和不具有PARK2敲除（KO）的等基因人诱导多能干细胞（iPSCs），通过比较代谢组学和超微结构和功能分析来研究parkin功能丧失的影响。PARK2 KO神经元表现出三羧酸（TCA）循环活性增加，线粒体超微结构紊乱，ATP消耗，糖酵解和肉毒碱代谢失调。这些扰动与氧化应激增加和抗氧化反应降低相结合。使用患者特异性ipsc衍生的神经元证实了PARK2 KO细胞的关键发现。总的来说，我们的数据描述了与帕金功能障碍相关的独特代谢组学特征，并表明将代谢组学与ipsc衍生的PD的多巴胺能神经元模型相结合是一种有价值的方法，可以获得对疾病发病机制的新见解。PARK2 （parkin）突变导致代谢失调，parkin功能障碍导致TCA循环活性增加和ATP消耗，parkin影响糖酵解和肉碱代谢，与parkin相关的能量扰动与氧化应激增加相结合。在这篇文章中，Okarmus及其同事发现，PARK2基因（parkin）的功能缺失突变导致代谢失调。具有这种突变的人类ipsc来源的神经元代谢组的变化伴随着线粒体和能量稳态的改变，氧化应激的增加和抗氧化反应的减少。这些发现对我们理解帕金森病的发病机制有重要的贡献。
PARK2 (parkin) mutations cause early-onset Parkinson's disease (PD). Parkin is an ubiquitin E3 ligase that participates in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain unknown. Here, we used isogenic human induced pluripotent stem cells (iPSCs) with and without PARK2 knockout (KO) to investigate the effect of parkin loss of function by comparative metabolomics supplemented with ultrastructural and functional analyses. PARK2 KO neurons displayed increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure, ATP depletion, and dysregulation of glycolysis and carnitine metabolism. These perturbations were combined with increased oxidative stress and a decreased anti-oxidative response. Key findings for PARK2 KO cells were confirmed using patient-specific iPSC-derived neurons. Overall, our data describe a unique metabolomic profile associated with parkin dysfunction and show that combining metabolomics with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis. PARK2 (parkin) mutations cause metabolic dysregulation Parkin dysfunction causes increased TCA cycle activity and ATP depletion Parkin affects glycolysis and carnitine metabolism Parkin-related energy perturbations are combined with increased oxidative stress In this article, Okarmus and colleagues show that loss-of-function mutations in the PARK2 gene (parkin) leads to metabolic dysregulation. Changes in the metabolome of human iPSC-derived neurons with such mutations were accompanied by altered mitochondrial and energy homeostasis, increased oxidative stress, and a reduced anti-oxidative response. These findings represent a significant contribution to our understanding of Parkinson's disease pathogenesis.
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通讯作者：
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