Accumulating Mitochondrial DNA Mutations Drive Premature Hematopoietic Aging Phenotypes Distinct from Physiological Stem Cell Aging

Norddahl, Gudmundur L.; Pronk, Cornelis Jan; Wahlestedt, Martin; Sten, Gerd; Nygren, Jens M.; Ugale, Amol; Sigvardsson, Mikael; Bryder, David

doi:10.1016/j.stem.2011.03.009

Cited by 229 publications

(227 citation statements)

References 40 publications

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“…The accumulation of mitochondrial mutations (and decreased mitochondrial function) does not affect HSC self-renewal but impairs normal differentiation of erythroid and B lineages. 23 These results suggest that hematopoietic progenitors are more severely affected by the accumulation of mitochondrial DNA (mtDNA) mutations than are HSCs, consistent with the increasing reliance of progenitors on intact mitochondrial function.…”

mentioning

confidence: 66%

Mitophagy in hematopoietic stem cells

Joshi

Kundu

2013

Autophagy

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mentioning

confidence: 66%

Mitophagy in hematopoietic stem cells

Joshi

Kundu

2013

Autophagy

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“…Upregulation of glycolysis by HIF-1α in HSCs increases pyruvate incorporation into the TCA cycle [10]. However, HSCs contain fewer mitochondria than differentiated cells [19,20], and mitochondrial morphology in HSCs is immature relative to that seen in differentiated cells, indicative of low mitochondrial membrane potential and low NADH levels. In fact, HSCs depend less on OXPHOS, based on findings that ATPdependent dye efflux activity in HSCs is maintained in the presence of an inhibitor of cytochrome oxidase [10].…”

Section: Pdh Regulation Of Metabolite Flux Into the Tca Cyclementioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…They also show an accelerated age-related loss of retinal function (Kong et al 2011). Interestingly, this high mitochondrial mutation load alters the ability of hematopoietic stem cell lineages to undergo appropriate differentiation, leading to defects such as anaemia and lymphopenia similar to those caused by the premature senescence of this compartment (Norddahl et al 2011). Hence loss of mtDNA integrity via loss of the proofreading function of polymerase γ is strongly associated with ageing.…”

Section: Mitochondrial Nucleasesmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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Accumulating Mitochondrial DNA Mutations Drive Premature Hematopoietic Aging Phenotypes Distinct from Physiological Stem Cell Aging

Cited by 229 publications

References 40 publications

Mitophagy in hematopoietic stem cells

Mitophagy in hematopoietic stem cells

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

The role of DNA exonucleases in protecting genome stability and their impact on ageing

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