scholarly journals Blood progenitor redox homeostasis through GABA control of TCA cycle in Drosophila hematopoiesis

2021 ◽  
Author(s):  
Manisha Goyal ◽  
Ajay Tomar ◽  
Sukanya Madhwal ◽  
Tina Mukherjee
Keyword(s):  
Progenitor Cells ◽  
Pyruvate Dehydrogenase ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Myeloid Cell ◽  
Tca Cycle ◽  
Lymph Gland ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hematopoietic Organ ◽  
Ros Homeostasis

AbstractThe importance of reactive oxygen species (ROS) in myeloid cell development and function is well-established. However, a comprehensive understanding of metabolic states controlling ROS levels during hematopoiesis remains elusive. Myeloid-like blood progenitor cells of the Drosophila larvae reside in a specialized hematopoietic organ called the lymph gland. We find that these progenitors in homeostasis, utilize TCA to generate ROS. Excessive activation of TCA however raises ROS levels causing them to precociously differentiate and leads to retardation of lymph gland size. Thus, to maintain ROS homeostasis, progenitor cells utilize systemically derived GABA. GABA internalization and catabolism via inhibiting hydroxy prolyl hydroxylase (Hph) activity, promotes pyruvate dehydrogenase kinase enzyme activity (PDK). PDK controls inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme, connecting pyruvate to TCA cycle and OXPHOS. Thus, by regulating PDK, GABA regulates progenitor TCA activity and ROS levels. In addition to this, GABA-catabolism/Hph axis via Hifα/Sima drives a glycolytic state in progenitor cells. The dual control established by GABA on PDK and Sima maintains progenitor cell metabolism and sustains ROS homeostasis necessary for their development. Taken together, our study demonstrates the metabolic underpinnings of GABA in myeloid ROS regulation and their development, the relevance of which may be broadly conserved.

scholarly journals Blood progenitor redox homeostasis through olfaction-derived systemic GABA in hematopoietic growth control in Drosophila

Development ◽  
2021 ◽  
Vol 149 (8) ◽  
Author(s):  
Manisha Goyal ◽  
Ajay Tomar ◽  
Sukanya Madhwal ◽  
Tina Mukherjee
Keyword(s):  
Progenitor Cells ◽  
Growth Retardation ◽  
Pyruvate Dehydrogenase ◽  
Redox Homeostasis ◽  
Growth Control ◽  
Lymph Gland ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hematopoietic Organ ◽  
Ros Homeostasis ◽  
Drosophila Larvae

ABSTRACT The role of reactive oxygen species (ROS) in myeloid development is well established. However, its aberrant generation alters hematopoiesis. Thus, a comprehensive understanding of events controlling ROS homeostasis forms the central focus of this study. We show that, in homeostasis, myeloid-like blood progenitor cells of the Drosophila larvae, which reside in a specialized hematopoietic organ termed the lymph gland, use TCA to generate ROS. However, excessive ROS production leads to lymph gland growth retardation. Therefore, to moderate blood progenitor ROS, Drosophila larvae rely on olfaction and its downstream systemic GABA. GABA internalization and its breakdown into succinate by progenitor cells activates pyruvate dehydrogenase kinase (PDK), which controls inhibitory phosphorylation of pyruvate dehydrogenase (PDH). PDH is the rate-limiting enzyme that connects pyruvate to the TCA cycle and to oxidative phosphorylation. Thus, GABA metabolism via PDK activation maintains TCA activity and blood progenitor ROS homeostasis, and supports normal lymph gland growth. Consequently, animals that fail to smell also fail to sustain TCA activity and ROS homeostasis, which leads to lymph gland growth retardation. Overall, this study describes the requirement of animal odor-sensing and GABA in myeloid ROS regulation and hematopoietic growth control.

scholarly journals Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1731 ◽  
Author(s):  
Carina Neitzel ◽  
Philipp Demuth ◽  
Simon Wittmann ◽  
Jörg Fahrer
Keyword(s):  
Colorectal Cancer ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Dietary Factors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Driver Mutations ◽  
The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

scholarly journals Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species

2012 ◽  
Vol 287 (42) ◽  
pp. 35153-35160 ◽  
Author(s):  
Thomas R. Hurd ◽  
Yvonne Collins ◽  
Irina Abakumova ◽  
Edward T. Chouchani ◽  
Bartlomiej Baranowski ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Reactive Oxygen ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Oxygen Species ◽  
Complex Activity ◽  
Cycle Enzyme ◽  
Dehydrogenase Complex

Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O2̇̄), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O2̇̄ production, such as may occur under nutrient excess and low ATP demand, the increase in O2̇̄ and H2O2 may provide feedback signals to modulate mitochondrial metabolism.

scholarly journals Targeting Endothelial Cell Metabolism by Inhibition of Pyruvate Dehydrogenase Kinase and Glutaminase-1

2020 ◽  
Vol 9 (10) ◽  
pp. 3308
Author(s):  
Céline A. Schoonjans ◽  
Barbara Mathieu ◽  
Nicolas Joudiou ◽  
Luca X. Zampieri ◽  
Davide Brusa ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Tumor Angiogenesis ◽  
Pyruvate Dehydrogenase ◽  
Umbilical Vein ◽  
Cell Metabolism ◽  
Tube Formation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Angiogenic Therapy ◽  
Umbilical Vein Endothelial Cells ◽  
Glutaminase 1

Targeting endothelial cell (EC) metabolism should impair angiogenesis, regardless of how many angiogenic signals are present. The dependency of proliferating ECs on glucose and glutamine for energy and biomass production opens new opportunities for anti-angiogenic therapy in cancer. The aim of the present study was to investigate the role of pyruvate dehydrogenase kinase (PDK) inhibition with dichloroacetate (DCA), alone or in combination with the glutaminase-1 (GLS-1) inhibitor, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), on Human umbilical vein endothelial cells (HUVECs) metabolism, proliferation, apoptosis, migration, and vessel formation. We demonstrated that both drugs normalize HUVECs metabolism by decreasing glycolysis for DCA and by reducing glutamate production for BPTES. DCA and BPTES reduced HUVECs proliferation and migration but have no impact on tube formation. While DCA increased HUVECs respiration, BPTES decreased it. Using both drugs in combination further reduced HUVECs proliferation while normalizing respiration and apoptosis induction. Overall, we demonstrated that DCA, a metabolic drug under study to target cancer cells metabolism, also affects tumor angiogenesis. Combining DCA and BPTES may reduce adverse effect of each drug alone and favor tumor angiogenesis normalization.

scholarly journals Molecular interaction studies on ellagic acid for its anticancer potential targeting pyruvate dehydrogenase kinase 3

RSC Advances ◽  
2019 ◽  
Vol 9 (40) ◽  
pp. 23302-23315 ◽  
Author(s):  
Rashmi Dahiya ◽  
Taj Mohammad ◽  
Preeti Gupta ◽  
Anzarul Haque ◽  
Mohamed F. Alajmi ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Ellagic Acid ◽  
Molecular Interaction ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Reversible Phosphorylation ◽  
Interaction Studies ◽  
Metabolic Switching ◽  
The Tca Cycle

PDK3 plays a central role in cancer through the reversible phosphorylation of PDC thereby blocking the entry of pyruvate into the TCA cycle. PDK3 mediated metabolic switching can be therapeutically targeted for glycolysis addicted cancers.

scholarly journals Drosophila as a Model to Study Cellular Communication Between the Hematopoietic Niche and Blood Progenitors Under Homeostatic Conditions and in Response to an Immune Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Ismaël Morin-Poulard ◽  
Yushun Tian ◽  
Nathalie Vanzo ◽  
Michèle Crozatier
Keyword(s):  
Blood Cell ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Lymph Gland ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Immune Stress

In adult mammals, blood cells are formed from hematopoietic stem progenitor cells, which are controlled by a complex cellular microenvironment called “niche”. Drosophila melanogaster is a powerful model organism to decipher the mechanisms controlling hematopoiesis, due both to its limited number of blood cell lineages and to the conservation of genes and signaling pathways throughout bilaterian evolution. Insect blood cells or hemocytes are similar to the mammalian myeloid lineage that ensures innate immunity functions. Like in vertebrates, two waves of hematopoiesis occur in Drosophila. The first wave takes place during embryogenesis. The second wave occurs at larval stages, where two distinct hematopoietic sites are identified: subcuticular hematopoietic pockets and a specialized hematopoietic organ called the lymph gland. In both sites, hematopoiesis is regulated by distinct niches. In hematopoietic pockets, sensory neurons of the peripheral nervous system provide a microenvironment that promotes embryonic hemocyte expansion and differentiation. In the lymph gland blood cells are produced from hematopoietic progenitors. A small cluster of cells called Posterior Signaling Centre (PSC) and the vascular system, along which the lymph gland develops, act collectively as a niche, under homeostatic conditions, to control the balance between maintenance and differentiation of lymph gland progenitors. In response to an immune stress such as wasp parasitism, lymph gland hematopoiesis is drastically modified and shifts towards emergency hematopoiesis, leading to increased progenitor proliferation and their differentiation into lamellocyte, a specific blood cell type which will neutralize the parasite. The PSC is essential to control this emergency response. In this review, we summarize Drosophila cellular and molecular mechanisms involved in the communication between the niche and hematopoietic progenitors, both under homeostatic and stress conditions. Finally, we discuss similarities between mechanisms by which niches regulate hematopoietic stem/progenitor cells in Drosophila and mammals.

Increased glutaminolytic flux and activation of mitochondrial metabolism by BCL2 hyperactivity in lymphoma

2017 ◽  
Author(s):  
Kirandeep Kaur ◽  
Simar Singh ◽  
Helma Zecena ◽  
Laurent Dejean ◽  
Fabian V. Filipp
Keyword(s):  
B Cell ◽  
Pyruvate Dehydrogenase ◽  
Metabolic Networks ◽  
Metabolic Flux ◽  
Cell Lymphoma ◽  
Pyruvate Dehydrogenase Complex ◽  
B Cell Lymphoma ◽  
Tca Cycle ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Phenotype

AbstractB-cell lymphoma 2 (BCL2) is an important apoptosis regulator during developmental and pathological states, and its overexpression is a key feature of several malignancies. Genomic data from The Cancer Genome Atlas (TCGA) reveals significant somatic copy number amplification, overexpression, and/or elevated protein activity of BCL2 in 50 % of diffuse large B-cell lymphoma (DLBC) patients. While its canonical role in mitochondria-directed apoptosis is well established, the effect of BCL2 on transcriptional and metabolic networks remains elusive. Using an established lymphocytic pro-B-cell line overexpressing BCL2, we identified dysregulated transcriptional and metabolic networks by transcriptomic profiling arrays. Elevated BCL2 levels affect transcription factor complexes and mitogenic programs of NF-κB/REL, HIF1A/ARNT, AP1, E2F, and STAT factors. Using stable isotope-assisted metabolic flux measurements we quantify that elevated BCL2 expression increases carbon utilization boosting cellular proliferation. Tumorigenic overexpression of BCL2 significantly increases glycolytic flux, glutaminolysis, and anaplerotic flux into the TCA cycle. At the same time, the mitochondrial acetyl-CoA pool is separated from the glycolytic one by inactivating the pyruvate dehydrogenase complex via transcriptional regulation of pyruvate dehydrogenase kinase (PDK3). As compensatory fuel, mitochondrial TCA cycle metabolism is supported by asparagine synthase (ASNS) and oxidative glutaminolysis creating targets for small molecule inhibition of glutaminase. Lymphoma cells overexpressing BCL2 contained more mitochondrial mass and were more sensitive to L-glutamine deprivation and glutaminase inhibition. Cells overexpressing a mutant BCL2 G145E, which is incapable of binding BH domain members, failed to increase proliferation, glycolysis, or glutaminolysis. Taken together, the oncogene BCL2 has the ability to ramp up a metabolic phenotype supporting proliferation independent of its anti-apoptotic role. The cellular model of BCL2 activation supports NF-KB-positive subtypes of DLBC and identifies metabolic bottlenecks with dependency on anaplerotic flux as an actionable BCL2 effector network in cancer.

scholarly journals Numerical modelling of the effects of cold atmospheric plasma on mitochondrial redox homeostasis and energy metabolism

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tomoyuki Murakami
Keyword(s):  
Energy Metabolism ◽  
Cell Fate ◽  
Cell Metabolism ◽  
Redox Homeostasis ◽  
Tca Cycle ◽  
Adenosine Diphosphate ◽  
Atmospheric Plasma ◽  
Regulation System ◽  
Acid Oxidation ◽  
Mitochondrial Functions

AbstractA biochemical reaction model clarifies for the first time how cold atmospheric plasmas (CAPs) affect mitochondrial redox homeostasis and energy metabolism. Fundamental mitochondrial functions in pyruvic acid oxidation, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation involving the respiratory chain (RC), adenosine triphosphate/adenosine diphosphate (ATP/ADP) synthesis machinery and reactive oxygen species/reactive nitrogen species (ROS/RNS)-mediated mechanisms are numerically simulated. The effects of CAP irradiation are modelled as 1) the influx of hydrogen peroxide (H$${}_{2}$$2O$${}_{2}$$2) to an ROS regulation system and 2) the change in mitochondrial transmembrane potential induced by RNS on membrane permeability. The CAP-induced stress modifies the dynamics of intramitochondrial H$${}_{2}$$2O$${}_{2}$$2 and superoxide anions, i.e., the rhythm and shape of ROS oscillation are disturbed by H$${}_{2}$$2O$${}_{2}$$2 infusion. Furthermore, CAPs control the ROS oscillatory behaviour, nicotinamide adenine dinucleotide redox state and ATP/ADP conversion through the reaction mixture over the RC, the TCA cycle and ROS regulation system. CAPs even induce a homeostatic or irreversible state transition in cell metabolism. The present computational model demonstrates that CAPs crucially affect essential mitochondrial functions, which in turn affect redox signalling, metabolic cooporation and cell fate decision of survival or death.

scholarly journals Hypoxic Exposure Increases Energy Expenditure by Increasing Carbohydrate Oxidation in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yeram Park ◽  
Deunsol Hwang ◽  
Hun-Young Park ◽  
Jisu Kim ◽  
Kiwon Lim
Keyword(s):  
Glucose Metabolism ◽  
Energy Expenditure ◽  
Pyruvate Dehydrogenase ◽  
Hypoxic Condition ◽  
Open Circuit ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hypoxic Exposure ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Aims. Hypoxic exposure improves glucose metabolism. We investigated to validate the hypothesis that carbohydrate (CHO) oxidation could increase in mice exposed to severe hypoxic conditions. Methods. Seven-week-old male ICR mice (n=16) were randomly divided into two groups: the control group (CON) was kept in normoxic condition (fraction of inspired O2=21%) and the hypoxia group (HYP) was exposed to hypoxic condition (fraction of inspired O2=12%, ≈altitude of 4,300 m). The CON group was pair-fed with the HYP group. After 3 weeks of hypoxic exposure, we measured respiratory metabolism (energy expenditure and substrate utilization) at normoxic conditions for 24 hours using an open-circuit calorimetry system. In addition, we investigated changes in carbohydrate mechanism-related protein expression, including hexokinase 2 (HK2), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), and regulator of the genes involved in energy metabolism (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α) in soleus muscle. Results. Energy expenditure (EE) and CHO oxidation over 24 hours were higher in the HYP group by approximately 15% and 34% (p<0.001), respectively. Fat oxidation was approximately 29% lower in the HYP group than the CON group (p<0.01). Body weight gains were significantly lower in the HYP group than in the CON group (CON vs. HYP; 1.9±0.9 vs. −0.3±0.9; p<0.001). Hypoxic exposure for 3 weeks significantly reduced body fat by approximately 42% (p<0.001). PDH and PGC1α protein levels were significantly higher in the HYP group (p<0.05). Additionally, HK2 was approximately 21% higher in the HYP group. Conclusions. Hypoxic exposure might significantly enhance CHO oxidation by increasing the expression of PDH and HK2. This investigation can be useful for patients with impaired glucose metabolism, such as those with type 2 diabetes.

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