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Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis

ABSTRACT: Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis

PROVIDER: PRJNA1167262 | ENA |

REPOSITORIES: ENA

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Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis

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:Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis

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UNG shapes the specificity of AID-induced somatic hypermutation

Project description:This SuperSeries is composed of the following subset Series: GSE39108: UNG shapes the specifity of AID-induced somatic hypermutation in non B cells GSE39114: UNG shapes the specifity of AID-induced somatic hypermutation in B cells Refer to individual Series

2012-07-04 | E-GEOD-39115 | biostudies-arrayexpress

Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis

Project description:Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis

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Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis (RNA-Seq)

Project description:Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis (RNA-Seq)

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Cells following mtDNA loss, or NAR1 repression

Project description:Expression analysis of cells the given amount of time after mtDNA was lost (or Nar1 expression was repressed) compared to pretreatment (or NAR1 being fully expressed). One time course experiment (Cells a given amount of time following mtDNA loss compared to cells with intact mtDNA), with 2 two condition experiments (Cells with the ATP1-111 genotype 27 hours following mtDNA loss compared to the same cells with intact mtDNA, and cells 27 hours following repression of NAR1 comared to cells expressing NAR1). Each data point had 3 biological replicates, and was dye-swapped. One replicate per array.

2010-06-21 | E-GEOD-15302 | biostudies-arrayexpress

Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis (rRNA 2'-O-me modification)

Project description:Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis (rRNA 2'-O-me modification)

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Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice

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

Pathogenic mtDNA mutations inhibit melanoma metastasis

Project description:We report the transcriptome profiles of A375 melanoma tumors containing distinct mtDNA mutations. This study was performed using subcutaneous tumors implanted into NSG mice, and identifies transcriptomice changes in response to pathogenic mtDNA mutations.

2024-10-25 | GSE276027 | GEO

Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for precise termination of mtDNA replication

Project description:The exact in vivo role for RNase H1 in mammalian mitochondria (mtDNA) has been much debated and we show here that it is essential for processing of RNA primers to provide site-specific initiation of mtDNA replication. Without RNase H1, mtDNA replication is instead initiated at non-canonical sites and becomes impaired. Furthermore, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain (HBD) of RNase H1 causing impaired mtDNA replication. In contrast to catalytically dead pathological variants of RNase H1, this mutant version has enhanced enzyme activity. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.

2022-07-13 | GSE199198 | GEO

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