Young and elderly fibroblast cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE67000 | GEO | 2015/03/18
SECONDARY ACCESSION(S): PRJNA278667
REPOSITORIES: GEO
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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: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: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.
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2007-08-04 | E-GEOD-1462 | biostudies-arrayexpress
Project description:Elderly atopic dermatitis is a subtype of AD defined by age (over 60 years), which has different clinical manifestations and distinct inflammatory patterns from AD in infants, children, and adolescents/adults. However, the molecular characteristics of elderly AD remain to be clarified.We sought to characterize the molecular features of skin lesions and peripheral blood mononuclear cells (PBMCs) in patients with AD across various age groups, focusing on elderly AD.We identified the molecular phenotypes of skin lesions and PBMCs in elderly individuals with AD. Fibroblasts, innate immune cells, and SASP might play important roles in the pathogenesis of elderly AD.
2024-02-23 | GSE256050 | 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:Generating mammalian cells with desired mtDNA sequences is enabling for studies of mitochondria, disease modeling, and potential regenerative therapies. MitoPunch, a high-throughput mitochondrial transfer device, produces cells with specific mtDNA-nDNA combinations by transferring isolated mitochondria from mouse or human cells into primary or immortal mtDNA-deficient (p0) cells. Stable isolated mitochondrial recipient (SIMR) cells isolated in restrictive media permanently retain donor mtDNA and reacquire respiration. However, SIMR fibroblasts maintain a p0-like cell metabolome and transcriptome despite growth in restrictive media. We reprogram non-immortal SIMR fibroblasts into induced pluripotent stem cells (iPSCs) with subsequent differentiation into diverse functional cell types, including mesenchymal stem cells (MSCs), adipocytes, osteoblasts, and chondrocytes. Remarkably, following reprogramming and differentiation, SIMR fibroblasts molecularly and phenotypically resemble un-manipulated control fibroblasts carried through the same protocol. Thus, our MitoPunch ‘pipeline’ enables the production of SIMR cells with unique mtDNA-nDNA combinations for additional studies and applications in multiple cell types.
2020-12-29 | GSE115871 | GEO
Project description:Tumor cells without mitochondrial DNA (mtDNA) reconstitute oxidative phosphorylation (OXPHOS) by acquiring host mitochondria from stromal cells, but the reasons why functional respiration is crucial for tumorigenesis remain unclear. To address this issue, we used time-resolved analysis of the initial stages of tumor formation by cells devoid of mtDNA and genetic manipulations of components of OXPHOS. We show that pyrimidine biosynthesis, supported by respiration-linked dihydroorotate dehydrogenase (DHODH), is strictly required to overcome cell cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis.
2018-10-01 | E-MTAB-6150 | biostudies-arrayexpress
Project description:Mutations in the mitochondrial DNA (mtDNA) have been proposed to be essential for metabolic adaptation, and because metabolism is intrinsically associated with multiple disease states, including obesity, we hypothesized that changes in the mtDNA would significantly influence adiposity and gene expression in response to diet. To test these predictions we used Mitochondrial-Nuclear eXchange mice, which have nuclear and mitochondrial genomes that have been exchanged from different M. musculus strains.
2018-09-12 | GSE86826 | 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