Transcriptomic and epigenetic characterization of PVT neurons in bipolar disorder model mouse.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE169212 | GEO | 2021/06/01
REPOSITORIES: GEO
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Project description:The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on the process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.
2024-10-28 | GSE278440 | 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: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:Pathogenic mutations in the catalytic DNA polymerase gamma (POLG1) gene result in the accumulation of mtDNA mutations, deletions and/or decrease of mtDNA copy number. These features interfere with proper functioning of the electron transport chain, mostly affecting metabolically active tissues such as the brain, the heart and the liver. So far, mechanisms underlying POLG pathogenesis are not fully understood. To identify general pathways influenced by mutant polymerase gamma, skeletal muscle gene expression profiles of six POLG1 patients and twelve controls were compared. Patient and control subject from three age categories (<10; 11-49; >50) were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.
2016-07-03 | E-GEOD-18715 | biostudies-arrayexpress
Project description:Pathogenic mutations in the catalytic DNA polymerase gamma (POLG1) gene result in the accumulation of mtDNA mutations, deletions and/or decrease of mtDNA copy number. These features interfere with proper functioning of the electron transport chain, mostly affecting metabolically active tissues such as the brain, the heart and the liver. So far, mechanisms underlying POLG pathogenesis are not fully understood. To identify general pathways influenced by mutant polymerase gamma, skeletal muscle gene expression profiles of six POLG1 patients and twelve controls were compared.
2016-01-01 | GSE18715 | 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. 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:RNAsequencing data from POLG D257A mutant mouse iPS (induced pluripotent stem) cells. These mice accumulate random point mutations in their mitochondrial genome and manifest progeric features. The reprogramming and phenotype of the cells is described in Hämäläinen et al. 2015, Cell reports, mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling. The goal of the study was to analyze altered gene expression profiles between mutant and wt iPS cells to identify altered biological pathways responsible for the stemness and proliferation defects seem in mtDNA mutator stem cells.
2019-09-24 | GSE133259 | 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