ATP turnover and glucose dependency in hematopoietic stem/progenitor cells are increased by proliferation and differentiation

Watanuki, S.; Kobayashi, Hiroshi; Sorimachi, Yuriko; Yamamoto, Masamichi; Okamoto, Shinichiro; Takubo, Keiyo

doi:10.1016/j.bbrc.2019.04.123

Cited by 10 publications

(7 citation statements)

References 22 publications

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“… 56 , 57 Activated HSCs increase the demands for ATP and further decrease their ATP level. 58 Apoptosis is a form of well-programmed cell death by forming apoptotic bodies, and it requires energy to complete this progress. 59 , 60 GSDME-mediated pyroptosis is a kind of necrosis, 34 and might demand little or no energy.…”

Section: Discussionmentioning

confidence: 99%

BECN1 modulates hematopoietic stem cells by targeting Caspase-3-GSDME-mediated pyroptosis

Yang

Wang

2020

Blood Science

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Hematopoietic stem cells (HSCs) maintain the blood system throughout the lifespan. However, the molecular mechanism maintaining HSC character remains not fully understood. In this study, we observed that the targeted deletion of Becn1 disrupts the blood system and impairs the reconstitution capacity of HSCs. Interestingly, Becn1 deletion did not lead to dysfunction of autophagy in HSCs, indicating a non-classical role of BECN1 in regulating HSCs function. While we observed the increase of Caspase-3-GSDME-mediated pyroptosis in Becn1 deficient hematopoietic stem and progenitor cells. Forced expression of the full-length GSDME compromises the function of HSCs. In brief, we identified a novel role of Becn1 in modulating HSCs by regulating pyroptosis, but not through autophagy. This study provides a new link between BECN1-Caspase-3-GSDME signaling and HSC maintenance.

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Section: Discussionmentioning

confidence: 99%

BECN1 modulates hematopoietic stem cells by targeting Caspase-3-GSDME-mediated pyroptosis

Yang

Wang

2020

Blood Science

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“…In particular, we observed that the ATRA-driven NB4 granulocytic differentiation depends both upon glycolysis and OXPHOS for ATP production; however, the relative contribution of glycolysis increases in a time-dependent manner during the process of maturation. Differentiated hematopoietic cells, including hematopoietic progenitor cells and granulocyte/monocyte progenitors, although generating ATP preferentially via OXPHOS, strongly rely on ATP produced by glycolysis [126]. This commitment to the Warburg metabolism may support the notion that the mitochondrial functions related to ATP production is reduced in granulocytes, mitochondria being primarily involved in maintaining the redox balance and promoting flux through the glycolytic pathway while avoiding commitment to the apoptotic process [127].…”

Section: Discussionmentioning

confidence: 78%

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Albanesi

Noguera

Banella

et al. 2020

Cells

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Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.

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“…Glucose is involved in the production of ATP within cells by glycolysis and the tricarboxylic acid cycle 34 . Therefore, we investigated the changes in intracellular ATP levels in both Cd‐treated HK‐2 cells and SLC2A4 ‐knockdown cells.…”

Section: Resultsmentioning

confidence: 99%

“…Glucose is involved in the production of ATP within cells by glycolysis and the tricarboxylic acid cycle. 34 Therefore, we F I G U R E 3 Effect of SLC2A2 expression on the sensitivity of HK-2 cells to Cd. A, SLC2A2 mRNA levels in HK-2 cells treated with Cd for 6 hours were examined by real-time RT-PCR.…”

Section: Atp Levels and CD Toxicitymentioning

confidence: 99%

Cadmium toxicity mediated by the inhibition of SLC2A4 expression in human proximal Tubule cells

2020

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Cadmium (Cd) is an environmental contaminant that causes renal toxicity. We have previously demonstrated that Cd induces renal toxicity by altering transcriptional activities. In this study, we show that Cd markedly inhibited the activity of transcription factor MEF2A in HK‐2 human proximal tubule cells, which generated significant cytotoxicity in the cells. This reduction in the nuclear levels of MEF2A protein may be involved in the Cd‐induced inhibition of MEF2A activity. We also demonstrate that one of the glucose transporters, GLUT4, was downregulated not only by Cd treatment but also by MEF2A knockdown. Knockdown of SLC2A4, encoding GLUT4, eliminated both cell viability and Cd toxicity. Cd treatment or SLC2A4 deficiency reduced the cellular concentration of glucose. Therefore, the suppression of SLC2A4 expression, which mediates the reduction in cellular glucose, is involved in Cd toxicity. The Cd toxicity induced by the reduction in GLUT4 may be associated with a reduction of cellular ATP levels in HK‐2 cells. The levels of Slc2a4 mRNA in the kidney of mice exposed to Cd for 6 or 12 months were significantly lower than those in the control group. These results demonstrate that Cd exerts its cytotoxicity through the suppression in SLC2A4 expression and the subsequent inhibition of MEF2A transcriptional activity. Cd‐induced suppression of SLC2A4 expression also reduces cellular ATP levels, partly by reducing glucose levels. This study suggests that the glucose transporter plays an important role in the renal toxicity of Cd, and provides a crucial breakthrough in our understanding of the mechanism of Cd toxicity.

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ATP turnover and glucose dependency in hematopoietic stem/progenitor cells are increased by proliferation and differentiation

Cited by 10 publications

References 22 publications

BECN1 modulates hematopoietic stem cells by targeting Caspase-3-GSDME-mediated pyroptosis

BECN1 modulates hematopoietic stem cells by targeting Caspase-3-GSDME-mediated pyroptosis

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

Cadmium toxicity mediated by the inhibition of SLC2A4 expression in human proximal Tubule cells

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