RNAseq data from mtDNA mutator induced pluripotent stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE133259 | GEO | 2019/09/24
REPOSITORIES: GEO
Similar Datasets
Project description:The goal of this study was to characterize gene expression profiles of wild-type (WT) and POLG D257A/D257A mutator (POLG mutator) macrophages at rest and 6 hours after lipopolysaccharide (LPS) challenge.
2021-04-13 | GSE171960 | GEO
Project description:Mitochondrial DNA (mtDNA) mutations may contribute to aging and age-related disorders. Previously, we created mice expressing a proofreading-deficient version of the mtDNA polymerase gamma (Polg) which accumulate age-related mtDNA mutations and display premature aging. Here we performed microarray gene expression profiling to identify mtDNA mutation-responsive genes in the cochlea of aged mitochondrial mutator mice. Age-related accumulation of mtDNA mutations was associated with transcriptional alternations consistent with reduced inner ear function, mitochondrial dysfunction, neurodegeneration, and reduced cell structural modulation. Hearing assessment and histopathological results confirmed that aged PolgD257A/D257A (D257A) mice exhibited moderate hearing loss and severe cochlear degenerations. Age-related accumulation of mtDNA mutations also resulted in alternations in gene expression consistent with induction of apoptosis, proteolysis, stress response, and reduced DNA repair. TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay confirmed that the cochleae from aged D257A mice showed significantly more TUNEL positive cells compared to wild-type (WT) mice. The levels of cleaved caspase-3 were also found to increase in the cochleae of aged D257A mice. These observations provide evidence that age-related accumulation of mtDNA mutations is associated with apoptotic cell death in aged cochlea. Our results provide the first global view of molecular events associated with mtDNA mutations in postmitotic tissue, and suggest that apoptosis is the major mechanism of mtDNA mediated cell death in the development of age-related hearing disorder. Keywords: disease state analysis
2007-05-18 | GSE4866 | GEO
Project description:We have performed both proteomic and transcriptomic analyses of the brains of one-year old Polg mutator mice. As part of this analysis, we generated RNA-Seq data from RNA isolated from one cerebral hemisphere of these mice. mRNA levels and protein abundance levels were compared in this study. 11 samples of RNA isolated from mouse cerebral hemisphere. 7 Polg D257A/D257A, 1 Polg D257A/WT, and 3 Polg WT/WT. The samples were collected from one-year old male mice.
2015-02-18 | E-GEOD-55188 | biostudies-arrayexpress
Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocyticanemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease. We used microarrays to identify expression profiles and pathways that are differentially activated or suppressed in Ter119+ bone marrow cells isolated from phlebotomized wildtype or Polg mutant mice
2015-04-21 | E-GEOD-57761 | biostudies-arrayexpress
Project description:Mitochondrial DNA (mtDNA) mutations may contribute to aging and age-related disorders. Previously, we created mice expressing a proofreading-deficient version of the mtDNA polymerase gamma (Polg) which accumulate age-related mtDNA mutations and display premature aging. Here we performed microarray gene expression profiling to identify mtDNA mutation-responsive genes in the cochlea of aged mitochondrial mutator mice. Age-related accumulation of mtDNA mutations was associated with transcriptional alternations consistent with reduced inner ear function, mitochondrial dysfunction, neurodegeneration, and reduced cell structural modulation. Hearing assessment and histopathological results confirmed that aged PolgD257A/D257A (D257A) mice exhibited moderate hearing loss and severe cochlear degenerations. Age-related accumulation of mtDNA mutations also resulted in alternations in gene expression consistent with induction of apoptosis, proteolysis, stress response, and reduced DNA repair. TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) assay confirmed that the cochleae from aged D257A mice showed significantly more TUNEL positive cells compared to wild-type (WT) mice. The levels of cleaved caspase-3 were also found to increase in the cochleae of aged D257A mice. These observations provide evidence that age-related accumulation of mtDNA mutations is associated with apoptotic cell death in aged cochlea. Our results provide the first global view of molecular events associated with mtDNA mutations in postmitotic tissue, and suggest that apoptosis is the major mechanism of mtDNA mediated cell death in the development of age-related hearing disorder. Experiment Overall Design: To determine the effects of age-related accumulation of mtDNA mutations, each WT sample (n = 5) was compared to each D257A sample (n = 5), generating a total of twenty-five pairwise comparisons. Genes with significantly altered expression levels were sorted into gene ontology biological process categories. Experiment Overall Design: Gene expression change was called statistically significant when at least one gene was called present in a group, the P value was < 0.0500, FC was > 1.1, and FDR was > 30.00 for identification of mtDNA mutations-induced genes. Experiment Overall Design: Affymetrix standard spike controls were used in all experiments (eukaryotic hybridization control kit). Quality control measures were not used. No replicates were done. Dye swap was not used.
2008-11-07 | E-GEOD-4866 | biostudies-arrayexpress
Project description:RNAseq data from mtDNA mutator induced pluripotent stem cells
| PRJNA550531 | ENA
Project description:Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wildtype and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.
2015-04-21 | GSE57761 | GEO
Project description:Accumulating evidences suggest a link between mitochondrial dysfunction and female reproduction decline. To directly and systematically figure out the influence of mitochondrial DNA (mtDNA) mutation on oocyte quality and embryo development, we used an mtDNA mutator mouse model (D257A) that harbors a proofreading-deficient version of PolgA. Here we showed that D257A mice developed a profound reduction of fertility at 19-week of age, and accumulated twofold more increase in the levels of point mutations in oocyte mtDNA. Following ovarian hyper-stimulation, we found oocyte numbers retrieved from WT and D257A mice were comparable until 19 weeks of age, while with a half reduced number of oocyte ovulated in D257A mice thereafter. We further found the oocyte quality based on mitochondrial distribution, meiotic spindle assembly, chromosomal segregation and ATP content at 19 weeks of age was identical in both group. Meanwhile, the ovulated oocytes can initiate and sustain early embryo development after in vitro fertilization, and reach the blastocyst stage with no obvious defects compared to WTs. Of note, post-implantation developmental defects were observed in D257A embryos, as revealed by fetal growth retardation and decreased ratios of pups delivered. Furthermore, genome-wide methylation analysis revealed global hypomethylation across the genome of D257A oocytes, with a dramatic reduce in genome repetitive-elements, like DNA transposon, LINEs and SINEs regions. In conclusion, our study presents the direct experimental investigation of the effect of mtDNA mutation on oocyte and embryo competence, and demonstrates altered DNA methylation in oocyte may represent a critical mechanism that mediates the phenotypic defects of mtDNA mutation in post-implantation development.
2020-12-31 | GSE147547 | GEO
Project description:To identify and analyze mtDNA mutation-responsive genes, a comparison of gastrocnemius muscle tissues from WT (control) and D257A mice was conducted. We examined changes in gene expression in the muscle associated with mtDNA mutations. 1) Types of experiments: a) Effect of mitochondrial DNA (mtDNA) mutations b) Effect of aging c) WT (13 month-old Polg+/+ mice) vs. D257A (13 month-old PolgD257A/D257A) mice 2) Experimental factors: a) Type of gene: PolgD257A/D257A b) Time (age) 3) Number of hybridizations in the study: ~10 4) A common reference RNA was not used. 5) Quality control measures were not used. No replicates were done. Dye swap was not used.
2010-05-27 | E-GEOD-21189 | biostudies-arrayexpress
Project description:Exercise is a fundamental component of human health that is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of endurance exercise on human health are well established, the molecular mechanisms responsible for these observations remain unclear. Endurance exercise reduces the accumulation of mitochondrial DNA (mtDNA) mutations, alleviates multisystem pathology, and increases the lifespan of the mtDNA mutator mouse model of aging, in which the proof-reading capacity of mitochondrial polymerase gamma (POLG1) is deficient. Clearly, exercise recruited a POLG1-independent mtDNA repair pathway to induce these adaptations, a novel finding as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here we investigate the identity of this pathway, and show that endurance exercise prevents mitochondrial oxidative damage, attenuates telomere erosion, and mitigates cellular senescence and apoptosis in mtDNA mutator mice. Unexpectedly, we observe translocation of tumour suppressor protein p53 to mitochondria in response to endurance exercise that facilitates mtDNA mutation repair. Indeed, endurance exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, and mitigate premature mortality in mtDNA mutator mice with muscle-specific deletion of p53. Our data establish an exciting new role for p53 in exercise-mediated maintenance of the mtDNA genome, and presents mitochondrially-targeted p53 as a novel therapeutic modality for aging-associated diseases of mitochondrial etiology. Microarray analysis of gene expression from skeletal muscle (quadriceps femoris) from Mus musculus. N=23 samples per treatment were analysed for whole transcriptiome gene expression profile using NimbleGen Arrays. The treatment groups included wild-type C57Bl/6J mice as the control group, then two treatment groups which both contained homozygous knock-in mtDNA mutator mice (PolG; PolgAD257A/D257A). Once group of these heterozygous knock out mice received regular endurance exercise sessions while the other group remained sedentraty for 6 months. The control group specimens were wild-type litter mates to the transgenic knockout mice.
2015-12-11 | E-GEOD-75869 | biostudies-arrayexpress