POLG mutations lead to abnormal mitochondrial remodeling during neural differentiation of human pluripotent stem cells via SIRT3/AMPK pathway inhibition
Year: 2022
Type: dataset
Abstract: We showed previously that POLG 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 POLG 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 POLG mutations lead to abnormal mitochondrial remodeling in early neural development due to the downregulation of these pathways.
Source: Figshare
Institutions: BGI Group (China), The University of Texas MD Anderson Cancer Center, Anhui Agricultural University, Shandong University, Harbin Medical University, Shanghai Jiao Tong University, Chinese Academy of Sciences, Peking University, Renji Hospital, XinHua Hospital, Beijing Institute of Genomics, First Affiliated Hospital of Xinjiang Medical University, Guangdong Academy of Agricultural Sciences, Nanfang Hospital, Nanjing Drum Tower Hospital, Honghe University, First Affiliated Hospital of GuangXi Medical University, Ningxia Medical University, Shanghai East Hospital, Chengdu Second People's Hospital, Shuguang Hospital, Beijing Proteome Research Center, Ningbo First Hospital, University of Bergen, Southern Medical University, Zhejiang University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4394541021