生物
诱导多能干细胞
神经干细胞
复合杂合度
线粒体
线粒体DNA
柠檬酸循环
表型
杂合子优势
突变
粒体自噬
粒线体疾病
细胞生物学
氧化磷酸化
分子生物学
遗传学
基因型
癌症研究
干细胞
基因
细胞凋亡
生物化学
新陈代谢
自噬
胚胎干细胞
作者
Hong Yang,Cecilie Katrin Kristiansen,Anbin Chen,Gonzalo S. Nido,Lena Elise Høyland,Mathias Ziegler,Gareth J. Sullivan,Laurence A. Bindoff,Kristina Xiao Liang
标识
DOI:10.1016/j.expneurol.2023.114429
摘要
Diseases caused by POLG mutations are the most common form of mitochondrial diseases and associated with phenotypes of varying severity. Clinical studies have shown that patients with compound heterozygous POLG mutations have a lower survival rate than patients with homozygous mutations, but the molecular mechanisms behind this remain unexplored. Using an induced pluripotent stem cell (iPSC) model, we investigate differences between homozygous and compound heterozygous genotypes in different cell types, including patient-specific fibroblasts, iPSCs, and iPSC-derived neural stem cells (NSCs) and astrocytes. We found that compound heterozygous lines exhibited greater impairment of mitochondrial function in NSCs than homozygous NSCs, but not in fibroblasts, iPSCs, or astrocytes. Compared with homozygous NSCs, compound heterozygous NSCs exhibited more severe functional defects, including reduced ATP production, loss of mitochondrial DNA (mtDNA) copy number and complex I expression, disturbance of NAD+ metabolism, and higher ROS levels, which further led to cellular senescence and activation of mitophagy. RNA sequencing analysis revealed greater downregulation of mitochondrial and metabolic pathways, including the citric acid cycle and oxidative phosphorylation, in compound heterozygous NSCs. Our iPSC-based disease model can be widely used to understand the genotype-phenotype relationship of affected brain cells in mitochondrial diseases, and further drug discovery applications.
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