Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.
Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong Province, China.
Cell Cycle. 2022 Jun;21(11):1178-1193. doi: 10.1080/15384101.2022.2044136. Epub 2022 Mar 17.
We showed previously that mutations cause major changes in mitochondrial function, including loss of mitochondrial respiratory chain (MRC) complex I, mitochondrial DNA (mtDNA) depletion and an abnormal NAD/NADH ratio in both neural stem cells (NSCs) and astrocytes differentiated from induced pluripotent stem cells (iPSCs). In the current study, we looked at mitochondrial remodeling as stem cells transit pluripotency and during differentiation from NSCs to both dopaminergic (DA) neurons and astrocytes comparing the process in POLG-mutated and control stem cells. We saw that mitochondrial membrane potential (MMP), mitochondrial volume, ATP production and reactive oxygen species (ROS) changed in similar ways in POLG and control NSCs, but mtDNA replication, MRC complex I and NAD metabolism failed to remodel normally. In DA neurons differentiated from NSCs, we saw that mutations caused failure to increase MMP and ATP production and blunted the increase in mtDNA and complex I. Interestingly, mitochondrial remodeling during astrocyte differentiation from NSCs was similar in both POLG-mutated and control NSCs. Further, we showed downregulation of the SIRT3/AMPK pathways in POLG-mutated cells, suggesting that mutations lead to abnormal mitochondrial remodeling in early neural development due to the downregulation of these pathways. [Figure: see text].
我们之前的研究表明， 突变会导致线粒体功能发生重大变化，包括线粒体呼吸链（MRC）复合物 I 的丧失、线粒体 DNA（mtDNA）耗竭以及诱导多能干细胞（iPSC）分化而来的神经干细胞（NSC）和星形胶质细胞中 NAD/NADH 比例的异常。在本研究中，我们观察了线粒体重塑，因为干细胞在向多能性过渡以及从 NSC 分化为多巴胺能（DA）神经元和星形胶质细胞的过程中，比较了 POLG 突变和对照干细胞中的这一过程。我们发现，POLG 和对照 NSC 中的线粒体膜电位（MMP）、线粒体体积、ATP 产生和活性氧（ROS）以相似的方式发生变化，但 mtDNA 复制、MRC 复合物 I 和 NAD 代谢未能正常重塑。在从 NSC 分化而来的 DA 神经元中，我们发现 突变导致 MMP 和 ATP 产生增加失败，mtDNA 和复合物 I 的增加减弱。有趣的是，从 NSC 分化而来的星形胶质细胞中，线粒体重塑在 POLG 突变和对照 NSC 中是相似的。此外，我们还发现 POLG 突变细胞中 SIRT3/AMPK 途径下调，表明 突变导致这些途径下调，导致早期神经发育中异常的线粒体重塑。[图：见正文]。
