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POLG genotype influences degree of mitochondrial dysfunction in iPSC derived neural progenitors, but not the parent iPSC or derived glia
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 mol...
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Published in: | Experimental neurology 2023-07, Vol.365, p.114429-114429, Article 114429 |
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Main Authors: | , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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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•Compound heterozygous POLG mutants exhibit greater impairment of mitochondrial function than homozygotes in NSCs.•Greater mitochondrial defects in compound heterozygous POLG NSCs lead to cellular senescence and activation of mitophagy.•Cellular senescence in heterozygous POLG NSCs is mediated by p-SIRT1 and activation of mitophagy is regulated by BNIP3.•Compound heterozygous POLG NSCs lead to a lower potential to differentiate into DA neurons than homozygous NSCs. |
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ISSN: | 0014-4886 1090-2430 |
DOI: | 10.1016/j.expneurol.2023.114429 |