Somatic mtDNA Mutation Burden Shapes Metabolic Plasticity in Leukemogenesis
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ABSTRACT:
PROVIDER: PRJNA1167262 | ENA |
REPOSITORIES: ENA
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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: Not available
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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
Project description:Mitochondrial tRNA-derived fragments link mtDNA variation to metastatic burden
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Project description:Mitochondrial tRNA-derived fragments link mtDNA variation to metastatic burden [lung]
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Project description:Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to ageing remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature ageing. However, this model cannot resolve whether the ageing phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic OXPHOS dysfunction to a progressive immune response, characterized by upregulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses and ageing.
2026-07-28 | PXD080411 | Pride
Project description:Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to ageing remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature ageing. However, this model cannot resolve whether the ageing phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic OXPHOS dysfunction to a progressive immune response, characterized by upregulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses and ageing.
2026-07-24 | GSE336233 | 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
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