Characterization of mitochondrial and metabolic alterations induced by trisomy 21 during neural differentiation.
Characterization of mitochondrial and metabolic alterations induced by trisomy 21 during neural differentiation.
复制标题
神经分化过程中 21 三体性诱导的线粒体和代谢改变的表征。
DOI：
10.1016/j.freeradbiomed.2023.01.009
复制
发表时间：
2023
影响因子：
7.4
通讯作者：
Roede,JamesR
中科院分区：
文献类型：
--
作者：
Prutton,KendraM;Marentette,JohnO;Maclean,KennethN;Roede,JamesR
细胞氧化还原状态通过能量代谢控制和ROS产生指导诱导多能干细胞（iPSC）的分化。由于氧化应激和线粒体功能障碍在唐氏综合征（DS）中已被广泛报道，我们评估了DS iPSC向神经祖细胞（NPC）神经分化过程中的线粒体表型和能量代谢。我们的结果表明，在DS iPSC中线粒体网络的早期成熟和NADPH氧化酶4（NOX4）表达的升高。DS细胞在分化过程中也不能从糖酵解过渡到氧化磷酸化。具体而言，DS NPC显示出增加的能量需求，这在其线粒体和糖酵解对线粒体窘迫的反应中是有限的。此外，DS iPSC和NPC非线粒体耗氧量受到NOX抑制的显著影响。总之，这些数据建立在以前的证据，加速神经分化的DS与细胞氧化还原状态。我们证明了线粒体和非线粒体ROS来源在DS背景下影响分化时间的潜力，这可能导致这种情况下的发育缺陷。
Cellular redox state directs differentiation of induced pluripotent stem cells (iPSC) by energy metabolism control and ROS generation. As oxidative stress and mitochondrial dysfunction have been extensively reported in Down syndrome (DS), we evaluated mitochondrial phenotypes and energy metabolism during neural differentiation of DS iPSCs to neural progenitor cells (NPCs). Our results indicate early maturation of mitochondrial networks and elevated NADPH oxidase 4 (NOX4) expression in DS iPSCs. DS cells also fail to transition from glycolysis to oxidative phosphorylation during differentiation. Specifically, DS NPCs show an increased energetic demand that is limited in their mitochondrial and glycolytic response to mitochondrial distress. Additionally, DS iPSC and NPC non-mitochondrial oxygen consumption was significantly impacted by NOX inhibition. Together, these data build upon previous evidence of accelerated neural differentiation in DS that correlates with cellular redox state. We demonstrate the potential for mitochondrial and non-mitochondrial ROS sources to impact differentiation timing in the context of DS, which could contribute to developmental deficits in this condition.