Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE310683 | GEO | 2026/01/27
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:It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether MSCs transfer mitochondria to the cells under several different conditions of mitochondrial dysfunction, including human pathogenic mitochondrial DNA (mtDNA) mutations. Using biochemical selection methods, we found that exponentially growing cells in restrictive media (uridine and bromodeoxyuridine [BrdU]+) after coculture of MSCs (uridine-independent and BrdU-sensitive) and 143B-derived cells with severe mitochondrial dysfunction induced by either long-term ethidium bromide treatment or short-term rhodamine 6G (R6G) treatment (uridine-dependent but BrdU-resistant). The exponentially growing cells had nuclear DNA fingerprint patterns identical to 143B, and a sequence of mtDNA identical to the MSCs. Since R6G causes rapid and irreversible damage to mitochondria without the removal of mtDNA, the mitochondrial function appears to be restored through a direct transfer of mitochondria rather than mtDNA alone. Conditioned media, which were prepared by treating mtDNA-less 143B 0 cells under uridine-free condition, induced increased chemotaxis in MSC, which was also supported by transcriptome analysis. A chemotaxis inhibitory agent blocked mitochondrial transfer phenomenon in the above condition. However, we could not find any evidence of mitochondrial transfer to the cells harboring human pathogenic mtDNA mutations (A3243G mutation or 4,977 bp deletion). Thus, the mitochondrial transfer is limited to the condition of a near total absence of mitochondrial function. Elucidation of the mechanism of mitochondrial transfer will help us create a potential “cell therapy-based mitochondrial restoration or mitochondrial gene therapy” for human diseases caused by mitochondrial dysfunction. time series
2011-11-22 | E-GEOD-33831 | biostudies-arrayexpress
Project description:Currently there is no treatment for mitochondrial disease, a group of devastating inherited disorders caused by mutations in mitochondrial DNA (mtDNA). Here we report a strategy to prevent the germline transmission of mitochondrial diseases. This technique is based on the specific elimination of mutated mtDNA through the use of mitochondria targeted nucleases. Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. A total of 4 samples were analyzed. Test samples were compared to sex-matched reference samples.
2015-04-23 | E-GEOD-67371 | 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: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 have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. In this study, we characterized mtDNA mutations in ovarian cancer patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels. To correlate the presence of mtDNA mutations and metabolic pathways that were modulated at the transcriptional level, RNA-seq analysis was performed in ascites-derived cells from 19 OC PDX (here named PDOVCA). Results indicated that mtDNA mutated (>50% VAF) PDX were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. Functional analysis demonstrated that mtDNA mutations modulated mitochondria activity, assembly capacity and morphology of mitochondrial complexes in PDX cells. Moreover, PDX cells bearing homoplasmic mtDNA mutations behave as glucose addicted and could barely survive glucose starvation in vitro. These findings led us to investigate whether mtDNA mutations correlated with response to anti-VEGF therapy, which was shown to reduce glucose availability in tumors. Strikingly, PDX bearing homoplasmic pathogenic mtDNA mutations had improved survival upon anti-VEGF treatment in mouse models, compared with PDX lacking mtDNA mutations or bearing them at low frequency. These results hint at mtDNA mutations as new biomarkers of response to antiangiogenic drugs.
2024-12-27 | GSE261674 | GEO
Project description:To identify mutations that occurred in the nuclear and mitochondrial DNA of the yeast subjected to mtDNA base editing or Mito-BE screen, we performed whole-genome sequencing of cultured yeast cells after isolation of mitochondrial DNA.
2024-11-01 | E-MTAB-13701 | biostudies-arrayexpress
Project description:Damage to the mitochondrial genome (mtDNA) severely affects the cell and causes disease. Mutations to mtDNA also accumulate throughout the lifespan of many organisms and may be a proximal cause of aging. There is no effective treatment for ailments caused by mtDNA mutation. Since mitochondrial function and biogenesis are controlled by the nutrient environment of the cell, it is possible that perturbation of conserved, nutrient-sensing pathways may successfully treat mitochondrial disease. Experiments using the tractable eukaryote Saccharomyces cerevisiae allow us to investigate the connection between nutrient-sensing and mitochondrial function. We have focused our current studies on the protein kinase A (PKA) pathway, which controls S. cerevisiae behavior according to glucose availability. We found that reduced PKA signaling can lead, in a background-dependent manner, to improved fitness after mtDNA loss. Specifically, over-expression of the cyclic AMP phosphodiesterase Pde2p, removal of PKA isoform Tpk3p, or ablation of other proteins promoting PKA activity leads to improved proliferation of cells deleted of the mitochondrial genome. Over-expression of Pde2p also suppresses the inviability of several mutants that normally cannot survive mtDNA loss. Moreover, Pde2p over-expression diminishes the nuclear transcriptional response to mtDNA damage, further supporting the idea that glucose sensation is harmful for cells lacking the mitochondrial genome. These findings are heavily dependent upon yeast genetic background. Interestingly, robust import of mitochondrial polytopic membrane proteins may be required in order for cells with no mtDNA to receive the full benefits of PKA reduction. Our findings support the idea that perturbation of nutrient-sensing pathways, and specifically the sensation of glucose, may benefit cells with dysfunctional mitochondria. Four experimental conditions were used: BY4743 (WT) cells containing empty pRS426 vector and containing mtDNA because EtBr was not used, BY4743 (WT) cells containing empty pRS426 vector and lacking mtDNA after 24 hours of treatment with 25 µg/ml ethidium bromide, BY4743 (WT) cells overexpressing TIP41 from plasmid pRS426 and lacking mtDNA after 24 hours of treatment with 25 µg/ml ethidium bromide, and BY4743 (WT) cells overexpressing PDE2 from plasmid pRS426 and lacking mtDNA after 24 hours of treatment with 25 µg/ml ethidium bromide. Two replicates were performed for each sample type.
2015-08-07 | E-GEOD-71252 | biostudies-arrayexpress
Project description:Mitochondrial dysfunction is a hallmark of cellular senescence. Mitochondrial DNA (mtDNA) functions as a damage-associated molecular pattern that activates the innate immune system when released extracellularly. We examined whether senescent cells release mtDNA into the extracellular space and the consequences of this exogenous mtDNA in innate immunity. Both primary senescent cells and tumor cells undergoing therapy-induced senescence release mtDNA into the extracellular space. In vivo cross-species xenograft models using human prostate cancer cells in immunocompromised mice demonstrated the selective uptake of human mtDNA by mouse polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) within the tumor microenvironment (TME). In vitro trans-well experiments confirmed the uptake of mtDNA by mouse PMN-MDSCs through extracellular vesicles (EVs). Internalized mtDNA enhanced the immunosuppressive activity of PMN-MDSCs via cGAS-STING-NF-_B activation, promoting tumor progression. Mechanistically, mtDNA released from senescent cells was mediated by voltage-dependent anion channels (VDAC), and pharmacological inhibition of VDAC reduced extracellular mtDNA levels, reversing PMN-MDSC-driven immunosuppression and improving the efficacy of chemotherapy in prostate cancer models. Thus, inhibiting mtDNA release may enable reprogramming of the immune suppressive microenvironment in patients treated with chemotherapy.
2025-03-24 | GSE290948 | GEO
Project description:Oxidative phosphorylation (OxPhos) within mitochondria relies on the coordinated synthesis of both nuclear- and mitochondrial-encoded protein subunits comprising the mitochondrial respiratory complexes (Complexes I–V). Mitochondrial DNA (mtDNA) encodes 13 proteins vital for Complex I, III, IV, and V function. Accumulated mutations in mtDNA are causally linked to aging and several age-related diseases, presumably as a consequence of impaired respiration. However, how high mtDNA mutation burden impinges on cellular bioenergetics across the major organ systems remains only partially resolved. Due to the growing links connecting mtDNA mutations to human pathophysiology, here we leveraged a comprehensive mitochondrial phenotyping platform to assess the phenotypic consequences of increased mtDNA mutation burden across tissues (brown adipose, brain, colon, heart, kidney, liver, lung, and bone marrow-derived mononuclear cells) of the mouse. Remarkably, despite widespread reductions in OxPhos protein expression, mitochondrial respiratory capacity under mixed substrate conditions was largely preserved across tissues. More detailed analysis revealed that NAD-linked respiration exhibited partial functional deficits in most tissues, consistent with functional deficiencies in complex I. In contrast, respiration routed from CII-CIII-CIV-CV remained intact. Together, these findings highlight Complex I as the primary functional consequence of mtDNA mutational load.
2026-02-19 | PXD068316 | JPOST Repository