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
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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: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
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Project description:How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using Mitochondrial-Nuclear eXchange (MNX) mice, we previously showed that mtDNA single nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences, suggesting a role for non-protein-coding loci. The only SNP correlating with these phenotypes resides in the gene encoding mitochondrial tRNA-Arginine (mt-tRNAArg (UCG), mt-TR). Here we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TR. Northern blotting revealed distinct tRF that are differentially expressed between lung and liver and between sexes. Small RNA sequencing failed to capture these tRF unless samples were pre-treated to enzymatically remove non-canonical RNA termini and base methylation. Focusing on fragments with complete homology to mt-TR, the two most abundant tRF align uniquely to the mitochondrial genome and share conserved cleavage sites. Together, these findings uncover mitochondrial-derived tRF as a previously unrecognized small RNA metastasis modifiers and expand the functional output of the mitochondrial genome, supporting a model in which mtDNA-encoded tRF contribute to phenotype modification.
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Project description:Phase separation-competent FBL shapes nucleolar function and translation in leukemogenesis
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Project description:How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using Mitochondrial-Nuclear eXchange (MNX) mice, we previously showed that mtDNA single nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences, suggesting a role for non-protein-coding loci. The only SNP correlating with these phenotypes resides in the gene encoding mitochondrial tRNA-Arginine (mt-tRNAArg (UCG), mt-TR). Here we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TR. Northern blotting revealed distinct tRF that are differentially expressed between lung and liver and between sexes. Small RNA sequencing failed to capture these tRF unless samples were pre-treated to enzymatically remove non-canonical RNA termini and base methylation. Focusing on fragments with complete homology to mt-TR, the two most abundant tRF align uniquely to the mitochondrial genome and share conserved cleavage sites. Together, these findings uncover mitochondrial-derived tRF as a previously unrecognized small RNA metastasis modifiers and expand the functional output of the mitochondrial genome, supporting a model in which mtDNA-encoded tRF contribute to phenotype modification.
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