Glucose Deficiency Research Articles

Glucose Starvation Blocks Translation at Multiple Levels

Deficiency of glucose, even under sufficient amino acid supply, turns off translation and promotes catabolic processes to aid cell survival. A recent report by Yoon etal. (2020) shows that glucose is required for the full activity of the leucyl-tRNA synthetase LARS1 and maintains mTORC1 function via LARS1 to enhance translation. Glucose starvation abolishes both effects via phosphorylation of LARS1 by the AMPK-ULK1 signaling pathway. This study supports the idea that glucose starvation inhibits translation at multiple levels.

JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy.

Rationale: Post-translational modifications have emerged as vital players in alterations to tumor metabolism, including amino acid metabolic reprogramming. Jumonji domain-containing protein 2B (JMJD2B) enhances colorectal cancer (CRC) cell survival upon glucose deficiency. In the present study, we hypothesized that JMJD2B affects tumor cell amino acid metabolism in CRC and consequently promotes survival of CRC cells upon glucose deprivation.Methods: Non-target metabolic profiling was used to evaluate the roles of JMJD2B in CRC cell metabolism under glucose starvation. The roles of amino acid alterations induced by JMJD2B on CRC cell survival were determined by cell viability, immunoblotting, and clonogenic assays, and flow cytometry. The underlying mechanisms by which JMJD2B affected CRC cell metabolism were assessed using immunofluorescence staining, chromatin immunoprecipitation assays, electron microscopy in CRC cell lines, and using xenograft models. The correlation between JMJD2B and LC3B expression in human CRC specimens was assessed using immunohistochemistry.Results: Profound metabolic reprogramming was detected in JMJD2B knockdown CRC cells under glucose deficiency, especially those involving amino acid metabolites. Silencing of JMJD2B reduced the levels of certain amino acids that were induced by glucose deficiency. Among these amino acids, asparagine (Asn), phenylalanine (Phe), and histidine (His) promoted CRC cell survival under glucose starvation when JMJD2B was knocked down. Mechanistically, downregulation of JMJD2B inhibited autophagy in CRC cells through epigenetic regulation of microtubule associated protein 1 light chain 3 beta (LC3B), and subsequently decreased intracellular amino acid (Asn, Phe, His) levels under glucose deprivation, thus suppressing the survival of CRC cells. Using a nude mouse xenograft model, we verified that inhibiting JMJD2B could decrease the levels of amino acids (Asn, Phe, His). In addition, the inhibitory effects of JMJD2B-knockdown on tumor growth and amino acids level were rescued by overexpression of LC3B. Furthermore, we observed that the high expression of LC3B was more likely detected in tissuses with high expression of JMJD2B (P < 0.001) in 60 human CRC tissues.Conclusion: These results indicated that JMJD2B sustained the intracellular amino acids derived from autophagy in CRC cells upon glucose deficiency, partly through epigenetic regulation of LC3B, thus driving the malignancy of CRC.

The effect of insulin resistance on mortality in critically ill patients in the intensive care unit

Background and Aims: Insulin resistance can be described as a subnormal biological response to a specific insulin concentration or deterioration of an accepted response to insulin in glucose homeostasis and deficiency of insulin response. The aim of this study is to evaluate the effect of insulin resistance on mortality in critically ill patients.Methods: Over 18-year-old and nondiabetic 150 patients that had been hospitalized in an intensive care unit (ICU) between September 2013 and October 2014 were enrolled in this study. The Acute Physiology and Chronic Health Enquiry II (APACHE II), Glasgow Coma Scale, and Richmond Agitation and Sedation Scale were calculated on the day of admission to the ICU, and following 4th day and 1st, 2nd, 3rd, and 4th weeks. Insulin resistance was calculated using the HOMA formula. Infection and other complications during ICU stay, the requirement of mechanical ventilation (MV), nutritional status (parenteral and/or enteral), vasopressor, steroid, and insulin treatment were also recorded. Patients followed in the ICU were recorded as survivors and nonsurvivors.Results: Glucose levels were found to be higher in nonsurvivor group at the 1st week and there was a significant positive relationship between APACHE II score and insulin resistance at the 3rd week. There was a significant relationship between mortality and requirement of MV, vasopressor medication, complications, and infection.Conclusion: We conclude that the effect of insulin resistance seems to affect the mortality in critically ill patients after at least a 3 weeks long follow-up time.

Severe calcium deficiency increased visceral fat accumulation, down-regulating genes associated with fat oxidation, and increased insulin resistance while elevating serum parathyroid hormone in estrogen-deficient rats

Menopause impairs calcium(Ca) metabolism and reduces bone mineral density (BMD), but the interaction of menopause with Ca deficiency in energy, glucose, lipid, and bone metabolism has not been studied. Herein we hypothesized that Ca deficiency at levels for post-menopausal women would impair energy, glucose, lipid, and bone metabolism in estrogen-deficient rats. This hypothesis was examined in ovariectomized (OVX) rats fed high-fat diets with different Ca levels for 12 weeks. OVX rats were allocated into either very low Ca (0.02%, VLCA), low Ca (0.7%, LCA), adequate Ca (1.18%, ACA, control), or excessive Ca (2.1%, EXCA). Sham-operated rats had the same diet as ACA (Normal-control). Ca intake was 37, 107, 190, and 311 mg/kg bw/d in the VLCA, LCA, ACA, and EXCA groups. The ACA group had higher serum parathyroid hormone concentrations than the Normal-control but were highest in VLCA. VLCA decreased BMD and lean body mass compared to ACA. Fasting serum glucose concentrations, even with higher serum insulin concentrations, were higher in the VLCA than ACA, indicating increased insulin resistance in VLCA. VLCA deteriorated glucose tolerance after oral glucose administration and impaired lipid profiles. LCA and EXCA had similar effects on metabolism as ACA, but LCA did not improve insulin sensitivity and lipid profiles as much as ACA. Expressions of hepatic genes related to fatty acid and cholesterol synthesis (FAS and SREBP-1c and HMGCR) were much higher in the VLCA than ACA and expressions of genes related fatty acid degradation(CPT1 and CYP7A1) were much lower in VLCA than ACA. In conclusion, we accepted the hypothesis. Very low Ca intake (350–400 mg/d as a human equivalent) exacerbated estrogen-deficiency-induced impairments of energy, glucose, and lipid metabolism by elevating serum parathyroid hormone levels and inducing visceral fat accumulation and insulin resistance in estrogen-deficient rats, but there was no added benefit of excessive Ca.

A549 폐암 세포주에서 AMPK/Akt/mTOR 신호 경로를 통한 소나무 담쟁이덩굴 에탄올 추출물의 Apoptosis 유도효과

Lung cancer can be caused by several environmental factors, such as smoking and urban and industrial pollution. Lung cancer also has a higher recurrence rate and a lower cure rate than other types of cancer. Parthenocissus tricuspidata (Siebold & Zucc.) Planch Extract (PTE) is known to have antioxidant, antidiabetic, and anti-inflammatory effects; however, its efficacy as an anticancer agent has not been reported. The purpose of this study was to investigate the effect of PTE on apoptosis-related proteins in A549 lung cancer cells and to determine how apoptosis is induced through the AMPactivated protein kinase (AMPK)/Akt/mTOR signaling pathway. AMPK is activated by metabolic stress, such as glucose deficiency, and induces apoptosis through the intrinsic pathway that activates tumor suppressor p53, thereby regulating the bcl-2 family protein, releasing cytochrome c from the mitochondria, and activating caspase. In addition, Akt plays an important role in the metabolism, growth, and survival of cancer cells. Inhibition of Akt induces apoptosis by regulating key signaling molecules, such as the mammalian target of rapamycin and tumor suppressor p53. In this study, we examined the effect of PTE on the apoptosis of A549 cells and determined how the regulation of apoptosis proteins through the intrinsic pathway is achieved. Our results demonstrated that PTE regulates bcl-2 proteins and induces apoptosis through the intrinsic pathway. In addition, AMPK and Akt inhibitors were treated to determine whether these apoptotic effects were dependent on AMPK and Akt.

Control of Translation at the Initiation Phase During Glucose Starvation in Yeast.

Glucose is one of the most important sources of carbon across all life. Glucose starvation is a key stress relevant to all eukaryotic cells. Glucose starvation responses have important implications in diseases, such as diabetes and cancer. In yeast, glucose starvation causes rapid and dramatic effects on the synthesis of proteins (mRNA translation). Response to glucose deficiency targets the initiation phase of translation by different mechanisms and with diverse dynamics. Concomitantly, translationally repressed mRNAs and components of the protein synthesis machinery may enter a variety of cytoplasmic foci, which also form with variable kinetics and may store or degrade mRNA. Much progress has been made in understanding these processes in the last decade, including with the use of high-throughput/omics methods of RNA and RNA:protein detection. This review dissects the current knowledge of yeast reactions to glucose starvation systematized by the stage of translation initiation, with the focus on rapid responses. We provide parallels to mechanisms found in higher eukaryotes, such as metazoans, for the most critical responses, and point out major remaining gaps in knowledge and possible future directions of research on translational responses to glucose starvation.

AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks

During hibernation, mammalian cells are exposed to severe environmental stressors such as low temperature, lowered O2 supply, and glucose deficiency. The cellular metabolic rate is markedly reduced for adapting to these conditions. AMP-activated protein kinase (AMPK) senses the cellular energy status and regulates metabolism. Therefore, we examined AMPK signaling in several brain regions and peripheral tissues in hibernating chipmunk. Eukaryotic elongation factor 2 (eEF2) is a downstream target of AMPK. Phosphorylation of eEF2, indicating its inactivation, is enhanced in the cerebral cortex of hibernating chipmunks. The study indicated that the sequential regulation of AMPK-mammalian target of rapamycin complex 1-eEF2 signaling was altered and protein synthesis ability was reduced in the cerebral cortex of hibernating chipmunks.

Computational evaluation of natural compounds as potential inhibitors of human PEPCK-M: an alternative for lung cancer therapy.

BackgroundLung cancer is the leading cause of cancer-related death worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) is the most common. Recently, the mitochondrial isoform of the enzyme phosphoenolpyruvate carboxykinase (HsPEPCK-M) was identified as responsible for the metabolic adaptation in the NSCLC allowing tumor growth even under conditions of glucose deficiency. This adaptation is possible due to the role of HsPEPCK-M in gluconeogenesis, converting the oxaloacetate to phosphoenolpyruvate in the presence of GTP, which plays an important role in the energetic support of these tumors. In this context, it was shown that the inhibition or knockdown of this enzyme was able to induce apoptosis in NSCLC under low glucose conditions.PurposeIn this study, novel putative inhibitors were proposed for the human PEPCK-M (HsPEPCK-M) based on a computer-aided approach.MethodsComparative modeling was used to generate 3D models for HsPEPCK-M. Subsequently, the set of natural compounds of the ZINC database was screened against HsPEPCK-M models using structure-based pharmacophore modeling and molecular docking approaches. The selected compounds were evaluated according to its chemical diversity and clustered based on chemical similarity.ResultsThe pharmacophore hypotheses, generated based on known PEPCK inhibitors, were able to select 7,124 candidate compounds. These compounds were submitted to molecular docking studies using three conformations of HsPEPCK-M generated by comparative modeling. The aim was to select compounds with high predicted binding affinity for at least one of the conformations of HsPEPCK-M. After molecular docking, 612 molecules were selected as potential inhibitors of HsPEPCK-M. These compounds were clustered according to their structural similarity. Chemical profiling and binding mode analyses of these compounds allowed the proposal of four promising compounds: ZINC01656421, ZINC895296, ZINC00895535 and ZINC02571340.ConclusionThese compounds may be considered as potential candidates for HsPEPCK-M inhibitors and may also be used as lead compounds for the development of novel HsPEPCK-M inhibitors.

Abstract 800: ESI-09 and HJC0197, known EPAC inhibitors, sensitize lung cancer cells to glucose starvation by uncoupling mitochondrial electron transport, leading to bioenergetic crisis

Abstract Cancer cells utilize aerobic glycolysis and proliferate continuously beyond the capacity of their blood supply, leading to microenvironmental stresses such as hypoxia, nutrient (glucose) deprivation and extracellular acidosis. We have previously showed that extracellular acidosis prevents glucose starvation-induced death of lung cancer cells by reducing glycolytic energy production and de novo protein/RNA synthesis that consume ATP (AACR 2018). This acidosis-dependent, glucose starvation-resistant, and ATP-saving phenotype is thought to serve as an adaptive response to glucose deprivation in cancer cells to survive an energy-restricted tumor microenvironment. In the present study, we screened small-molecule inhibitors to explore therapeutic reagents that can exert cytotoxicity against the glucose starvation-resistant phenotype in the lung cancer cell lines, A549 and H1299 cells. Among the various inhibitors tested, we found that ESI-09 and HJC0197, known as inhibitors of the exchanger protein directly activated by cAMP (EPAC), reduced the cellular ATP levels and survival under glucose deprivation stress under both acidic (pH 6.8) and neutral (pH 7.4) conditions. Interestingly, the ATP-reducing effect of ESI-09 and HJC0197 was not due to inhibition of the EPAC function, because the effect cannot be reproduced with other EPAC inhibitors, such as CE3F4, EPAC5376753 and ESI-05. Rather, the effect of ESI-09 and HJC0197 was attributed to their previously unknown action of uncoupling the mitochondrial electron transport chain (ETC). We found that ESI-09 and HJC0197 induced mitochondrial proton leak, causing ATP deficiency and cell death via the following three mechanisms: 1) decreased mitochondrial ATP production due to ETC uncoupling, 2) increased ATP consumption resulting from reversal of F0/F1-ATPsynthase/ATPase to maintain the mitochondrial membrane potential, and 3) glucose deficiency as a result of increased glucose consumption due to a compensatory stimulation of glycolytic ATP production. The energy-saving phenotype of cancer cells is thought to serve as an adaptive strategy that allows cell survival in an energy-restricted, acidic tumor microenvironment. Our results suggest that ESI-09 and HJC0197 disrupt bioenergetic tumor metabolism for energy homeostasis in both acidic and neutral microenvironment, and may exert a therapeutic effect against the starvation-resistant phenotype of cancer cells. The complete chemical structures of ESI-09 and HJC0197 will be divulged at the time of the presentation at the meeting. Citation Format: Yuki Iwai, Ryota Kikuchi, Hiroyuki Nakamura, Nobuyuki Koyama, Koichi Hagiwara, Kazutetsu Aoshiba. ESI-09 and HJC0197, known EPAC inhibitors, sensitize lung cancer cells to glucose starvation by uncoupling mitochondrial electron transport, leading to bioenergetic crisis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 800.

Effect of p-PAQR3Thr32 on PD-L1 expression and immune evasion in gastric cancer.

e15571 Background: Therapies targeted to the immune checkpoint mediated by PD-1 and PD-L1 show antitumor activity in some solid tumors. We have now examined PD-L1 expression and its regulation in gastric cancer with p-PAQR3Thr32 protein. Methods: The expression of PD-L1 at the protein and mRNA levels in gastric cancer cell lines was examined by flow cytometry, real-time RT-PCR and western blot analysis, respectively. The expression of PD-L1 and p-PAQR3Thr32 protein in 319 surgically resected gastric cancer specimens was evaluated by immunohistochemical analysis. Results: The PD-L1 expression level was higher in gastric cancer cell lines positive for p-PAQR3Thr32 protein induced by glucose starvation than in those negative for the p-PAQR3Thr32 protein. Forced expression of p-PAQR3Thr32 protein in gastric cancer cells markedly increased PD-L1 expression, whereas endogenous PD-L1 expression in p-PAQR3Thr32 protein positive gastric cancer cells was attenuated by treatment with PAQR3 siRNAs. Furthermore, expression of PD-L1 was downregulated by inhibitors of the IRF1 and STAT1 in IFNs-PDL1 signaling pathway in gastric cancer cells positive for p-PAQR3Thr32 protein. At clinical tissue level, the expression level of PD-L1 was positively associated with the presence of p-PAQR3Thr32 protein in gastric cancer specimens. Moreover, the expression level of p-PAQR3Thr32 protein was negatively correlated with CD3, CD8, GZMA (CD8 T cell secretory factor) and positively correlated with CD68 (macrophage marker). Conclusions: Our findings that p-PAQR3Thr32 protein induced by glucose deficiency upregulate PD-L1 by activating IFNs-PDL1 signaling pathway in gastric cancer reveal a direct link between p-PAQR3Thr32 protein and PD-L1 expression. It is suggested that p-PAQR3Thr32 protein may be involved in tumor immunosuppression by inhibiting the proliferation and activity of CD8 T cells in gastric cancer tissues.

Administration of Tonsil-Derived Mesenchymal Stem Cells Improves Glucose Tolerance in High Fat Diet-Induced Diabetic Mice via Insulin-Like Growth Factor-Binding Protein 5-Mediated Endoplasmic Reticulum Stress Modulation.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder accompanied by high blood glucose, insulin resistance, and relative insulin deficiency. Endoplasmic reticulum (ER) stress induced by high glucose and free fatty acids has been suggested as one of the main causes of β-cell dysfunction and death in T2DM. Stem cell-derived insulin-secreting cells were recently suggested as a novel therapy for diabetes. In the present study, we demonstrate the therapeutic potential of tonsil-derived mesenchymal stem cells (TMSCs) to treat high-fat diet (HFD)-induced T2DM. To explore whether TMSC administration can alleviate T2DM, TMSCs were intraperitoneally injected in HFD-induced T2DM mice once every 2 weeks. TMSC injection markedly improved glucose tolerance and glucose-stimulated insulin secretion and prevented HFD-induced pancreatic β-cell hypertrophy and cell death. In addition, TMSC injection relieved the ER-stress response and preserved gene expression related to glucose sensing and insulin secretion. Moreover, administration of TMSC-derived conditioned medium induced similar therapeutic outcomes, suggesting paracrine effects. Finally, proteomic analysis revealed high secretion of insulin-like growth factor-binding protein 5 by TMSCs, and its expression was critical for the protective effects of TMSCs against HFD-induced glucose intolerance and ER-stress response in pancreatic islets. TMSC administration can alleviate HFD-induced-T2DM via preserving pancreatic islets and their function. These results provide novel evidence of TMSCs as an ER-stress modulator that may be a novel, alternative cell therapy for T2DM.

Time-dependent cytotoxicity of dichloroacetate and metformin against Lewis lung carcinoma

To study time-dependent cytotoxicity of sodium dichloroacetate (DCA) and metformin (MTF) against metastatic tumor cells and action of these agents on tumor cell migration. In the study low metastatic LLC/R9variant of Lewis lung carcinoma was used. The number of living cells in the cytotoxic test was evaluated using sulforhodamine B after 1, 2and 3days of cell incubation in vitro. The parameters of the sensitivity of tumor cells to the action of DCA and MTF in vitro were calculated using nonlinear and linear regression of experimental data. The effect of DCA and MTF on cellular motility in vitro was evaluated using a Boyden chamber by calculation of the number of cells that migrated to the bottom side of the filter within 3days of incubation. The statistical analysis of the data was carried out with the use of descriptive methods, Student's t-criterion, nonlinear, and linear regression analysis. IC50of DCA was found to be equal to 50.8±7.6mM at the first day of incubation with LLC/R9cells and decreased by 1.9 (p < 0.05) and 2.1 (p < 0.05) times at the 2nd and 3rd days, respectively. Despite the almost identical ІC50at the 2nd and 3rd days, an increase in the incubation period of cells with DCA for up to 3days increased the C0parameter, which reflects the maximum concentration of the agent that does not exhibit cytotoxic effects, by 93% (p < 0.05) compared to this at the 2nd day (16.2 ± 1.4mM vs 8.4 ± 1.0mM, correspondently). Unlike DCA, the LLC/R9cell population was not homogeneous by the sensitivity to the action of MTF; at least at the 3rd day, an appearance of MTF-resistant subpopulation was observed, accounting for 35% of all cells. IC50of MTF was equal to 12.1 ± 0.6mM, and unlike DCA, this index progressively decreased at the 2nd and 3rd days by 1.4 (p < 0.05) and 9.3times (p < 0.05) respectively. Action of DCA at a concentration of 25mM alone and in combination with MTF at the concentrations of 0.1mM and 0.7mM resulted in an increase in cell migration by 65% (p < 0.05), 63% (p < 0.05) and 78.5% (p < 0.05), respectively. There was no significant effect of MTF on the tumor cell migration. The sensitivity of the metastatic Lewis lung carcinoma cells to the action of the modifiers of the energy metabolism increased significantly with an increase in the incubation period, apparently, primarily due to the shortage of nutrient substrates and, in particular, glucose, indicating the relevance of their combined use as well as with other agents, which promote the deficiency of glucose in the tumor microenvironment.

Curcumin Regulates the Progression of Colorectal Cancer via LncRNA NBR2/AMPK Pathway.

Objective:To identify the effect of curcumin on tumor suppression and the possible molecular pathways involved.Methods:The expression of long noncoding RNA neighbor of BRCA1 lncRNA 2 (NBR2) was quantified using reverse transcription-polymerase chain reaction on cultured colorectal cancer cells. Next, we used Western blot to measure the activation of adenosine monophosphate-activated protein kinase and mechanistic target of rapamycin kinase (mTOR) signaling molecules. Both cell proliferation and viability were measured via MTT assay, and the cell ratio and S phase were detected by BrdU assay. Colorectal cancer cells were pretreated with curcumin or transfected with shNBR2 or adenosine monophosphate-activated protein kinase inhibitor Compound C to examine the molecular pathway involved.Results:Current data showed that glucose deficiency increased the expression of NBR2 in colorectal cancer cells, and NBR2 knockdown affected the progression of colorectal cancer cells under glucose starvation conditions. When NBR2 was silenced in the treated colorectal cancer cells, the proliferation, the clone formation, and the percentage of S-phase cells suppressed by glucose deprivation were compromised. Furthermore, NBR2 knockdown could suppress glucose deprivation-induced adenosine monophosphate-activated protein kinase activation plus mTOR inactivation. Similarly, when colorectal cancer cells were treated with curcumin, the expression of NBR2 was significantly increased. NBR2 knockdown reversed curcumin-suppressed proliferation, clone formation, and the percentage of S-phase colorectal cancer cells. Furthermore, NBR2 knockdown abolished curcumin-induced activation of adenosine monophosphate-activated protein kinase and inactivation of the mTOR signaling pathway.Conclusion:This study revealed a novel mechanism by which long noncoding RNA NBR2 mediates curcumin suppression of colorectal cancer proliferation by activating adenosine monophosphate-activated protein kinase and inactivating the mTOR signaling pathway.

Resveratrol preserves mitochondrial function in a human post-mitotic cell model

Dysfunctions caused by genetic defects in the mitochondrial DNA (mtDNA) of humans are called mitochondrial diseases; however, mtDNA mutations are also associated with aging and age-related diseases. Here, we present an original cellular model that allows gathering information on molecules that might contrast or prevent mitochondrial dysfunctions and their related diseases. This model allowed us to show that resveratrol (RSV), a phytochemical present in food, exerts protective effects at low concentrations on resting human fibroblasts carrying dysfunctional respiratory chain Complex I. Cells were maintained both in resting condition, to mimic the high energy demanding post-mitotic tissues (serum absence and gramicidin presence), and under glucose deficiency to push the synthesis of ATP via oxidative phosphorylation. Pre-incubation with RSV prolonged the viability of the fibroblasts exposed to rotenone, a well-known specific inhibitor of the respiratory chain Complex I, and decreased mitochondrial fragmentation. It significantly prevented the oxidative phosphorylation impairment indirectly caused by the rotenone-mediated Complex I inhibition, allowing for an almost complete preservation of the cellular ATP level. Indeed, RSV limited the rotenone-induced reactive oxygen species increase, allowing for the maintenance of a functional mitochondrial membrane potential. These findings indicate the potential usage of resveratrol to prevent or possibly treat many disorders, in which the bioenergetic defects and oxidative stress are the primary (mitochondrial encephalomyopathy), or the secondary (age-related diseases) causes of the pathology; and to also assist cell senescence during aging.

Neuroprotective Effects of Melissa officinalis on Oxygen and Glucose Deficiency Induced Damage in Rat’s Brain Cortex Slices

Neuroprotective Effects of Melissa officinalis on Oxygen and Glucose Deficiency Induced Damage in Rat’s Brain Cortex Slices

Energy requirements in mammalian oogenesis

Oogenesis is a lengthy, multi-step process occurring in mammals yielding single or multiple oocytes capable of being fertilized upon interaction with male gametes. The overall process is highly complex in nature, starting in the primordial follicles, and its ultimate completion is preceded by the meiotic cycle. There are two major phases in oogenesis: the growth phase, followed by a maturation phase that requires relatively less time. Both phases require energy for the various metabolic processes of the oocytes. The energy requirements and the timing of maturation vary significantly among mammalian species. This review describes the variations in the mammalian oocytes development and their energy requirements. It covers the types of mitochondria, the distribution of their changes, and the metabolic processes occurring during the oogenesis in different mammalian species. Oocyte abnormalities associated with glucose deficiency in mammals are discussed, along with the role of fat and protein as alternative energy substrates. The review concludes with recommendations for future studies on oogenesis in mammalian species in the context of energy requirements.

The decisive role of fumarase: Responsive signaling to glucose deficiency

ABSTRACTOur recent study shows that AMPK normally phosphorates fumarase (FH) at Ser75 under glucose deprivation, resulting in FH-ATF2 complex formation that facilitates transcription for cell growth arrest. Meanwhile, O-GlcNAc transferase can compete with AMPK to O-GlcNAcylate FH. In tumor cells, FH is highly O-GlcNAcylated and is proinhibited from AMPK-ATF2 signaling.

CPT1C promotes human mesenchymal stem cells survival under glucose deprivation through the modulation of autophagy

Human mesenchymal stem cells (hMSCs) are widely used in regenerative medicine. In some applications, they must survive under low nutrient conditions engendered by avascularity. Strategies to improve hMSCs survival may be of high relevance in tissue engineering. Carnitine palmitoyltransferase 1 C (CPT1C) is a pseudoenzyme exclusively expressed in neurons and cancer cells. In the present study, we show that CPT1C is also expressed in hMSCs and protects them against glucose starvation, glycolysis inhibition, and oxygen/glucose deprivation. CPT1C overexpression in hMSCs did not increase fatty acid oxidation capacity, indicating that the role of CPT1C in these cells is different from that described in tumor cells. The increased survival of CPT1C-overexpressing hMSCs observed during glucose deficiency was found to be the result of autophagy enhancement, leading to a greater number of lipid droplets and increased intracellular ATP levels. In fact, inhibition of autophagy or lipolysis was observed to completely block the protective effects of CPT1C. Our results indicate that CPT1C-mediated autophagy enhancement in glucose deprivation conditions allows a greater availability of lipids to be used as fuel substrate for ATP generation, revealing a new role of CPT1C in stem cell adaptation to low nutrient environments.

AMPK Inhibits ULK1-Dependent Autophagosome Formation and Lysosomal Acidification via Distinct Mechanisms.

ABSTRACTAutophagy maintains metabolism in response to starvation, but each nutrient is sensed distinctly. Amino acid deficiency suppresses mechanistic target of rapamycin complex 1 (MTORC1), while glucose deficiency promotes AMP-activated protein kinase (AMPK). The MTORC1 and AMPK signaling pathways converge onto the ULK1/2 autophagy initiation complex. Here, we show that amino acid starvation promoted formation of ULK1- and sequestosome 1/p62-positive early autophagosomes. Autophagosome initiation was controlled by MTORC1 sensing glutamine, leucine, and arginine levels together. In contrast, glucose starvation promoted AMPK activity, phosphorylation of ULK1 Ser555, and LC3-II accumulation, but with dynamics consistent with a block in autophagy flux. We studied the flux pathway and found that starvation of amino acid but not of glucose activated lysosomal acidification, which occurred independently of autophagy and ULK1. In addition to lack of activation, glucose starvation inhibited the ability of amino acid starvation to activate both autophagosome formation and the lysosome. Activation of AMPK and phosphorylation of ULK1 were determined to specifically inhibit autophagosome formation. AMPK activation also was sufficient to prevent lysosome acidification. These results indicate concerted but distinct AMPK-dependent mechanisms to suppress early and late phases of autophagy.

RETRACTED ARTICLE: Mechanism of MALAT1 preventing apoptosis of vascular endothelial cells induced by oxygen–glucose deficiency and reoxidation

We, the Editors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Guoping Wang, Yuanbo Wu & Yuyou Zhu (2018) Mechanism of MALAT1 preventing apoptosis of vascular endothelial cells induced by oxygen–glucose deficiency and reoxidation. Artificial Cells, Nanomedicine, and Biotechnology, 46(sup1), 798–805, DOI: 10.1080/21691401.2018.1436065 Since publication, the authors repeated some of their experiments and found that under the same conditions they could not repeat the results reported in this paper. In addition, concerns were raised regarding the high degrees of similarity with the following previously published paper: Jia-Wei Xin & Yu-gang Jiang (2017) Long noncoding RNA MALAT1 inhibits apoptosis induced by oxygen-glucose deprivation and reoxygenation in human brain microvascular endothelial cells, Experimental and Therapeutic Medicine, 13(4), 1225–1234, DOI: 10.3892/etm.2017.4095. As this directly impacts the integrity of the reported results and conclusions, the authors alerted the issue to the Editor and Publisher and all have agreed to retract the article to ensure correction of the scholarly record. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.