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1.
CNS Neurosci Ther ; 30(8): e14913, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39123294

ABSTRACT

BACKGROUND: Hyperglycemia-induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear. OBJECTIVE: To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia-induced neuroinflammation and DNP and to explore potential therapeutic interventions. METHOD AND RESULTS: Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA-sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia-induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high-glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy-lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia-induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia-induced Sirt3 downregulation. CONCLUSION: Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Neuropathies , Down-Regulation , Glycolysis , Hyperglycemia , Mice, Inbred C57BL , Microglia , Sirtuin 3 , Animals , Sirtuin 3/metabolism , Sirtuin 3/genetics , Mice , Glycolysis/drug effects , Glycolysis/physiology , Down-Regulation/drug effects , Down-Regulation/physiology , Hyperglycemia/metabolism , Microglia/metabolism , Microglia/drug effects , Male , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Diabetic Neuropathies/metabolism , Inflammation/metabolism , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/etiology , Metformin/pharmacology
2.
Respir Res ; 25(1): 291, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39080660

ABSTRACT

Acute lung injury (ALI) is characterized by an unregulated inflammatory reaction, often leading to severe morbidity and ultimately death. Excessive inflammation caused by M1 macrophage polarization and pyroptosis has been revealed to have a critical role in ALI. Recent study suggests that glycolytic reprogramming is important in the regulation of macrophage polarization and pyroptosis. However, the particular processes underlying ALI have yet to be identified. In this study, we established a Lipopolysaccharide(LPS)-induced ALI model and demonstrated that blocking glycolysis by using 2-Deoxy-D-glucose(2-DG) significantly downregulated the expression of M1 macrophage markers and pyroptosis-related genes, which was consistent with the in vitro results. Furthermore, our research has revealed that Phosphoglycerate Kinase 1(PGK1), an essential enzyme in the glycolysis pathway, interacts with NOD-, LRR- and pyrin domain-containing protein 3(NLRP3). We discovered that LPS stimulation improves the combination of PGK1 and NLRP3 both in vivo and in vitro. Interestingly, the absence of PGK1 reduces the phosphorylation level of NLRP3. Based on in vitro studies with mice bone marrow-derived macrophages (BMDMs), we further confirmed that siPGK1 plays a protective role by inhibiting macrophage pyroptosis and M1 macrophage polarization. The PGK1 inhibitor NG52 suppresses the occurrence of excessive inflammation in ALI. In general, it is plausible to consider a therapeutic strategy that focuses on modulating the relationship between PGK1 and NLRP3 as a means to mitigate the activation of inflammatory macrophages in ALI.


Subject(s)
Acute Lung Injury , Macrophages , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein , Phosphoglycerate Kinase , Pyroptosis , Pyroptosis/physiology , Pyroptosis/drug effects , Animals , Phosphoglycerate Kinase/metabolism , Phosphoglycerate Kinase/genetics , Acute Lung Injury/pathology , Acute Lung Injury/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/enzymology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Mice , Macrophages/metabolism , Macrophages/drug effects , Macrophages/enzymology , Glycolysis/physiology , Glycolysis/drug effects , Male , Lipopolysaccharides/toxicity , Mice, Knockout , Cells, Cultured
3.
Biochem Pharmacol ; 226: 116415, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38972426

ABSTRACT

The hypoxic microenvironment in esophageal carcinoma is an important factor promoting the rapid progression of malignant tumor. This study was to investigate the lactylation of Axin1 on glycolysis in esophageal carcinoma cells under hypoxia exposure. Hypoxia treatment increases pan lysine lactylation (pan-kla) levels of both TE1 and EC109 cells. Meanwhile, ECAR, glucose consumption and lactate production were also upregulated in both TE1 and EC109 cells. The expression of embryonic stem cell transcription factors NANOG and SOX2 were enhanced in the hypoxia-treated cells. Axin1 overexpression partly reverses the induction effects of hypoxia treatment in TE1 and EC109 cells. Moreover, lactylation of Axin1 protein at K147 induced by hypoxia treatment promotes ubiquitination modification of Axin1 protein to promote glycolysis and cell stemness of TE1 and EC109 cells. Mutant Axin1 can inhibit ECAR, glucose uptake, lactate secretion, and cell stemness in TE1 and EC109 cells under normal or hypoxia conditions. Meanwhile, mutant Axin1 further enhanced the effects of 2-DG on inhibiting glycolysis and cell stemness. Overexpression of Axin1 also inhibited tumor growth in vivo, and was related to suppressing glycolysis. In conclusion, hypoxia treatment promoted the glycolysis and cell stemness of esophageal carcinoma cells, and increased the lactylation of Axin1 protein. Overexpression of Axin1 functioned as a glycolysis inhibitor, and suppressed the effects of hypoxia exposure in vitro and inhibited tumor growth in vivo. Mechanically, hypoxia induces the lactylation of Axin1 protein and promotes the ubiquitination of Axin1 to degrade the protein, thereby exercising its anti-glycolytic function.


Subject(s)
Axin Protein , Esophageal Neoplasms , Glycolysis , Mice, Nude , Humans , Axin Protein/metabolism , Axin Protein/genetics , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Glycolysis/physiology , Animals , Cell Line, Tumor , Mice , Mice, Inbred BALB C , Cell Hypoxia/physiology
4.
J Diabetes Complications ; 38(8): 108798, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38991492

ABSTRACT

AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear. METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures. RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups. CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.


Subject(s)
Diabetes Mellitus, Type 1 , Mitochondria, Muscle , Humans , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/physiopathology , Adult , Male , Female , Middle Aged , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiopathology , Glycolysis/physiology , Mitochondrial Diseases/metabolism , Mitochondrial Diseases/physiopathology , Mitochondrial Diseases/complications , Case-Control Studies , Magnetic Resonance Spectroscopy , Young Adult , Exercise/physiology
5.
PLoS Pathog ; 20(7): e1011909, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38976719

ABSTRACT

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, MNV-1, CR3, and CR6. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the viral lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified NS1/2 as the first viral molecule for RNA viruses that regulates glutaminolysis either directly or indirectly. This increases our fundamental understanding of virus-induced metabolic alterations and may lead to improvements in the cultivation of human NoVs.


Subject(s)
Caliciviridae Infections , Glutamine , Norovirus , Viral Nonstructural Proteins , Virus Replication , Norovirus/physiology , Virus Replication/physiology , Mice , Animals , Viral Nonstructural Proteins/metabolism , Viral Nonstructural Proteins/genetics , Glutamine/metabolism , Caliciviridae Infections/virology , Caliciviridae Infections/metabolism , Macrophages/virology , Macrophages/metabolism , Humans , Glutaminase/metabolism , Glycolysis/physiology , RAW 264.7 Cells
6.
Metabolism ; 158: 155974, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38996912

ABSTRACT

Acute kidney injury (AKI) is a frequent and severe complication of sepsis and is characterized by significant mortality and morbidity. However, the pathogenesis of septic acute kidney injury (S-AKI) remains elusive. Metabolic reprogramming, which was originally referred to as the Warburg effect in cancer, is strongly related to S-AKI. At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli. As the disease progresses, these cells revert to oxidative phosphorylation, thus promoting anti-inflammatory reactions and enhancing functional restoration. Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during S-AKI. In this review, we summarize the current understanding of the pathogenesis of metabolic reprogramming in S-AKI, with a focus on each cell type involved. By identifying relevant key regulatory factors, we also explored potential metabolic reprogramming-related therapeutic targets for the management of S-AKI.


Subject(s)
Acute Kidney Injury , Sepsis , Animals , Humans , Acute Kidney Injury/metabolism , Acute Kidney Injury/etiology , Acute Kidney Injury/therapy , Glycolysis/physiology , Metabolic Reprogramming/physiology , Sepsis/metabolism , Sepsis/complications
7.
J Physiol ; 602(14): 3449-3468, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38822814

ABSTRACT

The present study examined and compared the impact of exercise training on redox and molecular properties of human microvascular endothelial cells derived from skeletal muscle biopsies from sedentary recent (RPF, ≤ 5 years as postmenopausal) and late (LPF, ≥ 10 years as postmenopausal) postmenopausal females. Resting skeletal muscle biopsies were obtained before and after 8 weeks of intense aerobic exercise training for isolation of microvascular endothelial cells and determination of skeletal muscle angiogenic proteins and capillarisation. The microvascular endothelial cells were analysed for mitochondrial respiration and production of reactive oxygen species (ROS), glycolysis and proteins related to vascular function, redox balance and oestrogen receptors. Exercise training led to a reduced endothelial cell ROS formation (∼50%; P = 0.009 and P = 0.020 for intact and permeabilized cells (state 3), respectively) in RPF only, with no effect on endothelial mitochondrial capacity in either group. Basal endothelial cell lactate formation was higher (7%; P = 0.028), indicating increased glycolysis, after compared to before the exercise training period in RPF only. Baseline endothelial G protein-coupled oestrogen receptor (P = 0.028) and muscle capillarisation (P = 0.028) was lower in LPF than in RPF. Muscle vascular endothelial growth factor protein was higher (32%; P = 0.002) following exercise training in LPF only. Exercise training did not influence endothelial cell proliferation or skeletal muscle capillarisation in either group, but the CD31 level in the muscle tissue, indicating endothelial cell content, was higher (>50%; P < 0.05) in both groups. In conclusion, 8 weeks of intense aerobic exercise training reduces ROS formation and enhances glycolysis in microvascular endothelial cells from RPF but does not induce skeletal muscle angiogenesis. KEY POINTS: Late postmenopausal females have been reported to achieve limited vascular adaptations to exercise training. There is a paucity of data on the effect of exercise training on isolated skeletal muscle microvascular endothelial cells (MMECs). In this study the formation of reactive oxygen species in MMECs was reduced and glycolysis increased after 8 weeks of aerobic exercise training in recent but not late postmenopausal females. Late postmenopausal females had lower levels of G protein-coupled oestrogen receptor in MMECs and lower skeletal muscle capillary density at baseline. Eight weeks of intense exercise training altered MMEC properties but did not induce skeletal muscle angiogenesis in postmenopausal females.


Subject(s)
Endothelial Cells , Exercise , Muscle, Skeletal , Postmenopause , Reactive Oxygen Species , Humans , Female , Postmenopause/physiology , Muscle, Skeletal/blood supply , Muscle, Skeletal/physiology , Muscle, Skeletal/metabolism , Endothelial Cells/physiology , Endothelial Cells/metabolism , Exercise/physiology , Middle Aged , Reactive Oxygen Species/metabolism , Microvessels/physiology , Microvessels/cytology , Glycolysis/physiology , Aged , Receptors, Estrogen/metabolism
8.
Int J Biol Sci ; 20(8): 3113-3125, 2024.
Article in English | MEDLINE | ID: mdl-38904014

ABSTRACT

Aberrant activation of the PI3K/Akt pathway commonly occurs in cancers and correlates with multiple aspects of malignant progression. In particular, recent evidence suggests that the PI3K/Akt signaling plays a fundamental role in promoting the so-called aerobic glycolysis or Warburg effect, by phosphorylating different nutrient transporters and metabolic enzymes, such as GLUT1, HK2, PFKB3/4 and PKM2, and by regulating various molecular networks and proteins, including mTORC1, GSK3, FOXO transcription factors, MYC and HIF-1α. This leads to a profound reprogramming of cancer metabolism, also impacting on pentose phosphate pathway, mitochondrial oxidative phosphorylation, de novo lipid synthesis and redox homeostasis and thereby allowing the fulfillment of both the catabolic and anabolic demands of tumor cells. The present review discusses the interactions between the PI3K/Akt cascade and its metabolic targets, focusing on their possible therapeutic implications.


Subject(s)
Glucose , Neoplasms , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , Humans , Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Glucose/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Animals , Glycolysis/physiology
9.
FASEB J ; 38(10): e23703, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38805156

ABSTRACT

Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments. EFA detects mitochondrial respiration and glycolysis by measuring oxygen consumption and extracellular acidification rates, respectively. We show that both measurements positively correlate with sample sizes of a few centimeter-length renal tubules. The thick ascending limbs (TALs) and distal convoluted tubules (DCTs) critically utilize glucose/pyruvate as energy substrates, whereas proximal tubules (PTs) are significantly much less so. Acute inhibition of TALs' transport activity by ouabain treatment reduces basal and ATP-linked mitochondrial respiration. Chronic inhibition of transport activity by 2-week furosemide treatment or deletion of with-no-lysine kinase 4 (Wnk4) decreases maximal mitochondrial capacity. In addition, chronic inhibition downregulates mitochondrial DNA mass and mitochondrial length/density in TALs and DCTs. Conversely, gain-of-function Wnk4 mutation increases maximal mitochondrial capacity and mitochondrial length/density without increasing mitochondrial DNA mass. In conclusion, EFA is a sensitive and reliable method to investigate mitochondrial functions in isolated renal tubules. Transport activity tightly regulates mitochondrial bioenergetics and biogenesis to meet the energy demand in renal tubules. The system allows future investigation into whether and how mitochondria contribute to tubular remodeling adapted to changes in transport activity.


Subject(s)
Energy Metabolism , Kidney Tubules , Mitochondria , Animals , Mice , Mitochondria/metabolism , Kidney Tubules/metabolism , Male , Mice, Inbred C57BL , Oxygen Consumption , Organelle Biogenesis , Biological Transport , Glycolysis/physiology , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics
10.
Biochem Pharmacol ; 225: 116294, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38754557

ABSTRACT

Aerobic glycolysis is a hallmark of hepatocellular carcinoma (HCC). Dihydroartemisinin (DHA) exhibits antitumor activity towards liver cancer. Our previous studies have shown that DHA inhibits the Warburg effect in HCC cells. However, the mechanism still needs to be clarified. Our study aimed to elucidate the interaction between YAP1 and GLUT1-mediated aerobic glycolysis in HCC cells and focused on the underlying mechanisms of DHA inhibiting aerobic glycolysis in HCC cells. In this study, we confirmed that inhibition of YAP1 expression lowers GLUT1-mediated aerobic glycolysis in HCC cells and enhances the activity of CD8+T cells in the tumor niche. Then, we found that DHA was bound to cellular YAP1 in HCC cells. YAP1 knockdown inhibited GLUT1-mediated aerobic glycolysis, whereas YAP1 overexpression promoted GLUT1-mediated aerobic glycolysis in HCC cells. Notably, liver-specific Yap1 knockout by AAV8-TBG-Cre suppressed HIF-1α and GLUT1 expression in tumors but not para-tumors in DEN/TCPOBOP-induced HCC mice. Even more crucial is that YAP1 forms a positive feedback loop with GLUT1-mediated aerobic glycolysis, which is associated with HIF-1α in HCC cells. Finally, DHA reduced GLUT1-aerobic glycolysis in HCC cells through YAP1 and prevented the binding of YAP1 and HIF-1α. Collectively, our study revealed the mechanism of DHA inhibiting glycolysis in HCC cells from a perspective of a positive feedback loop involving YAP1 and GLUT1 mediated-aerobic glycolysis and provided a feasible therapeutic strategy for targeting enhanced aerobic glycolysis in HCC.


Subject(s)
Artemisinins , Carcinoma, Hepatocellular , Glucose Transporter Type 1 , Glycolysis , Liver Neoplasms , YAP-Signaling Proteins , Artemisinins/pharmacology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Animals , Glucose Transporter Type 1/metabolism , Glucose Transporter Type 1/genetics , Glucose Transporter Type 1/antagonists & inhibitors , Glycolysis/drug effects , Glycolysis/physiology , Liver Neoplasms/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , YAP-Signaling Proteins/metabolism , Humans , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Feedback, Physiological/drug effects , Cell Line, Tumor , Transcription Factors/metabolism , Transcription Factors/genetics , Male , Mice, Inbred C57BL
11.
Appl Physiol Nutr Metab ; 49(8): 1100-1114, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38710106

ABSTRACT

This study investigated sex-specific differences in high-energy phosphate, glycolytic, and mitochondrial enzyme activities and also metabolite transporter protein levels in the skeletal muscles of adult (5 months old), middle-aged (12 months old), and advanced-aged (24 months old) mice. While gastrocnemius glycogen content increased with age regardless of sex, gastrocnemius triglyceride levels increased only in advanced-aged female mice. Aging decreased creatine kinase and adenylate kinase activities in the plantaris muscle of both sexes and in the soleus muscle of male mice but not in female mice. Irrespective of sex, phosphofructokinase and lactate dehydrogenase (LDH) activities decreased in the plantaris and soleus muscles. Additionally, hexokinase activity in the plantaris muscle and LDH activity in the soleus muscle decreased to a greater extent in aged male mice compared with those in aged female mice. Mitochondrial enzyme activities increased in the plantaris muscle of aged female mice but did not change in male mice. The protein content of the glucose transporter 4 in the aged plantaris muscle and fatty acid translocase/cluster of differentiation 36 increased in the aged plantaris and soleus muscles of both sexes, with a significantly higher content in female mice. These findings suggest that females possess a better ability to maintain metabolic enzyme activity and higher levels of metabolite transport proteins in skeletal muscle during aging, despite alterations in lipid metabolism. Our data provide a basis for studying muscle metabolism in the context of age-dependent metabolic perturbations and diseases that affect females and males differently.


Subject(s)
Aging , Muscle, Skeletal , Animals , Muscle, Skeletal/metabolism , Female , Male , Aging/metabolism , Mice , Glycogen/metabolism , Glucose Transporter Type 4/metabolism , Adenylate Kinase/metabolism , L-Lactate Dehydrogenase/metabolism , Sex Factors , Creatine Kinase/metabolism , Hexokinase/metabolism , Triglycerides/metabolism , Phosphofructokinases/metabolism , Glycolysis/physiology
12.
Biol Pharm Bull ; 47(5): 905-911, 2024.
Article in English | MEDLINE | ID: mdl-38692867

ABSTRACT

Viruses require host cells to replicate and proliferate, which indicates that viruses hijack the cellular machinery. Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4-positive T cells, and efficiently uses cellular proteins to replicate. Cells already have proteins that inhibit the replication of the foreign HIV-1, but their function is suppressed by viral proteins. Intriguingly, HIV-1 infection also changes the cellular metabolism to aerobic glycolysis. This phenomenon has been interpreted as a cellular response to maintain homeostasis during viral infection, yet HIV-1 efficiently replicates even in this environment. In this review, we discuss the regulatory role of glycolytic enzymes in viral replication and the impact of aerobic glycolysis on viral infection by introducing various host proteins involved in viral replication. Furthermore, we would like to propose a "glyceraldehyde-3-phosphate dehydrogenase-induced shock (G-shock) and kill strategy" that maximizes the antiviral effect of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to eliminate latently HIV-1-infected cells.


Subject(s)
Glycolysis , HIV Infections , HIV-1 , Virus Replication , Humans , HIV-1/physiology , Glycolysis/physiology , HIV Infections/virology , HIV Infections/metabolism , HIV Infections/immunology , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism
13.
Biochem Pharmacol ; 224: 116247, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38697311

ABSTRACT

Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.


Subject(s)
Antineoplastic Agents , Carcinoma, Renal Cell , Dual Specificity Phosphatase 6 , Glycolysis , Kidney Neoplasms , Proto-Oncogene Proteins c-akt , Sunitinib , Humans , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Sunitinib/pharmacology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Glycolysis/drug effects , Glycolysis/physiology , Cell Line, Tumor , Proto-Oncogene Proteins c-akt/metabolism , Animals , Dual Specificity Phosphatase 6/metabolism , Dual Specificity Phosphatase 6/genetics , Antineoplastic Agents/pharmacology , Mice , Mice, Nude , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Male
14.
NPJ Syst Biol Appl ; 10(1): 55, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38789545

ABSTRACT

Aerobic glycolysis, or the Warburg effect, is used by cancer cells for proliferation while producing lactate. Although lactate production has wide implications for cancer progression, it is not known how this effect increases cell proliferation and relates to oxidative phosphorylation. Here, we elucidate that a negative feedback loop (NFL) is responsible for the Warburg effect. Further, we show that aerobic glycolysis works as an amplifier of oxidative phosphorylation. On the other hand, quiescence is an important property of cancer stem cells. Based on the NFL, we show that both aerobic glycolysis and oxidative phosphorylation, playing a synergistic role, are required to achieve cell quiescence. Further, our results suggest that the cells in their hypoxic niche are highly proliferative yet close to attaining quiescence by increasing their NADH/NAD+ ratio through the severity of hypoxia. The findings of this study can help in a better understanding of the link among metabolism, cell cycle, carcinogenesis, and stemness.


Subject(s)
Cell Proliferation , Feedback, Physiological , Glycolysis , Neoplastic Stem Cells , Oxidative Phosphorylation , Warburg Effect, Oncologic , Humans , Glycolysis/physiology , Feedback, Physiological/physiology , Neoplastic Stem Cells/metabolism , Cell Proliferation/physiology , Neoplasms/metabolism , NAD/metabolism , Lactic Acid/metabolism , Models, Biological , Cell Line, Tumor , Cell Cycle/physiology
15.
Diabetes ; 73(6): 856-863, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38768366

ABSTRACT

An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy ß-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)-driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of ß-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of ß-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane-associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.


Subject(s)
Glucose , Insulin Secretion , Insulin-Secreting Cells , Insulin , KATP Channels , Oxidative Phosphorylation , Insulin-Secreting Cells/metabolism , Humans , Glucose/metabolism , KATP Channels/metabolism , KATP Channels/genetics , Insulin Secretion/physiology , Animals , Insulin/metabolism , Glycolysis/physiology , Models, Biological , Adenosine Triphosphate/metabolism
16.
BMC Med ; 22(1): 189, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38715017

ABSTRACT

BACKGROUND: Sleep loss is a common public health problem that causes hyperalgesia, especially that after surgery, which reduces the quality of life seriously. METHODS: The 48-h sleep restriction (SR) mouse model was created using restriction chambers. In vivo imaging, transmission electron microscopy (TEM), immunofluorescence staining and Western blot were performed to detect the status of the blood-spinal cord barrier (BSCB). Paw withdrawal mechanical threshold (PWMT) was measured to track mouse pain behavior. The role of infiltrating regulatory T cells (Tregs) and endothelial cells (ECs) in mouse glycolysis and BSCB damage were analyzed using flow cytometry, Western blot, CCK-8 assay, colorimetric method and lactate administration. RESULTS: The 48-h SR made mice in sleep disruption status and caused an acute damage to the BSCB, resulting in hyperalgesia and neuroinflammation in the spinal cord. In SR mice, the levels of glycolysis and glycolysis enzymes of ECs in the BSCB were found significantly decreased [CON group vs. SR group: CD31+Glut1+ cells: p < 0.001], which could cause dysfunction of ECs and this was confirmed in vitro. Increased numbers of infiltrating T cells [p < 0.0001] and Treg population [p < 0.05] were detected in the mouse spinal cord after 48-h SR. In the co-cultured system of ECs and Tregs in vitro, the competition of Tregs for glucose resulted in the glycolysis disorder of ECs [Glut1: p < 0.01, ENO1: p < 0.05, LDHα: p < 0.05; complete tubular structures formed: p < 0.0001; CCK8 assay: p < 0.001 on 24h, p < 0.0001 on 48h; glycolysis level: p < 0.0001]. An administration of sodium lactate partially rescued the function of ECs and relieved SR-induced hyperalgesia. Furthermore, the mTOR signaling pathway was excessively activated in ECs after SR in vivo and those under the inhibition of glycolysis or co-cultured with Tregs in vitro. CONCLUSIONS: Affected by glycolysis disorders of ECs due to glucose competition with infiltrating Tregs through regulating the mTOR signaling pathway, hyperalgesia induced by 48-h SR is attributed to neuroinflammation and damages to the barriers, which can be relieved by lactate supplementation.


Subject(s)
Endothelial Cells , Glucose , Hyperalgesia , Sleep Deprivation , Spinal Cord , T-Lymphocytes, Regulatory , Animals , T-Lymphocytes, Regulatory/immunology , Mice , Glucose/metabolism , Endothelial Cells/metabolism , Spinal Cord/metabolism , Spinal Cord/pathology , Male , Sleep Deprivation/complications , Glycolysis/physiology , Disease Models, Animal , Mice, Inbred C57BL
17.
Glia ; 72(8): 1374-1391, 2024 08.
Article in English | MEDLINE | ID: mdl-38587131

ABSTRACT

Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type-specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also "funnel" lactate through their "myelinic" channels between gap junction-coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.


Subject(s)
Axons , Glycolysis , L-Lactate Dehydrogenase , Oligodendroglia , Animals , Oligodendroglia/metabolism , Axons/metabolism , L-Lactate Dehydrogenase/metabolism , L-Lactate Dehydrogenase/genetics , Glycolysis/physiology , Mice , Down-Regulation/physiology , Mice, Inbred C57BL , Lactate Dehydrogenase 5/metabolism , Astrocytes/metabolism , Astrocytes/ultrastructure , Mice, Transgenic , Isoenzymes/metabolism , Isoenzymes/genetics , Gap Junctions/metabolism , Gap Junctions/ultrastructure , Mice, Knockout
18.
Curr Opin Nephrol Hypertens ; 33(4): 361-367, 2024 07 01.
Article in English | MEDLINE | ID: mdl-38572729

ABSTRACT

PURPOSE OF REVIEW: Disruptions of phosphate homeostasis are associated with a multitude of diseases with insufficient treatments. Our knowledge regarding the mechanisms underlying metazoan phosphate homeostasis and sensing is limited. Here, we highlight four major advancements in this field during the last 12-18 months. RECENT FINDINGS: First, kidney glycolysis senses filtered phosphate, which results in the release of glycerol 3-phosphate (G-3-P). Circulating G-3-P then stimulates synthesis of the phosphaturic hormone fibroblast growth factor 23 in bone. Second, the liver serves as a postprandial phosphate reservoir to limit serum phosphate excursions. It senses phosphate ingestion and triggers renal excretion of excess phosphate through a nerve-dependent mechanism. Third, phosphate-starvation in cells massively induces the phosphate transporters SLC20A1/PiT1 and SLC20A2/PiT2, implying direct involvement of cellular phosphate sensing. Under basal phosphate-replete conditions, PiT1 is produced but immediately destroyed, which suggests a novel mechanism for the regulation of PiT1 abundance. Fourth, Drosophila melanogaster intestinal cells contain novel organelles called PXo bodies that limit intracellular phosphate excursions. Phosphate starvation leads to PXo body dissolution, which triggers midgut proliferation. SUMMARY: These studies have opened novel avenues to dissect the mechanisms that govern metazoan phosphate sensing and homeostasis with the potential to identify urgently needed therapeutic targets.


Subject(s)
Homeostasis , Phosphates , Humans , Animals , Phosphates/metabolism , Homeostasis/physiology , Kidney/metabolism , Fibroblast Growth Factor-23 , Liver/metabolism , Glycolysis/physiology
19.
J Neurosci ; 44(20)2024 May 15.
Article in English | MEDLINE | ID: mdl-38565291

ABSTRACT

Microglia undergo two-stage activation in neurodegenerative diseases, known as disease-associated microglia (DAM). TREM2 mediates the DAM2 stage transition, but what regulates the first DAM1 stage transition is unknown. We report that glucose dyshomeostasis inhibits DAM1 activation and PKM2 plays a role. As in tumors, PKM2 was aberrantly elevated in both male and female human AD brains, but unlike in tumors, it is expressed as active tetramers, as well as among TREM2+ microglia surrounding plaques in 5XFAD male and female mice. snRNAseq analyses of microglia without Pkm2 in 5XFAD mice revealed significant increases in DAM1 markers in a distinct metabolic cluster, which is enriched in genes for glucose metabolism, DAM1, and AD risk. 5XFAD mice incidentally exhibited a significant reduction in amyloid pathology without microglial Pkm2 Surprisingly, microglia in 5XFAD without Pkm2 exhibited increases in glycolysis and spare respiratory capacity, which correlated with restoration of mitochondrial cristae alterations. In addition, in situ spatial metabolomics of plaque-bearing microglia revealed an increase in respiratory activity. These results together suggest that it is not only glycolytic but also respiratory inputs that are critical to the development of DAM signatures in 5XFAD mice.


Subject(s)
Glucose , Homeostasis , Mice, Transgenic , Microglia , Animals , Microglia/metabolism , Microglia/pathology , Mice , Homeostasis/physiology , Glucose/metabolism , Male , Female , Humans , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/genetics , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics , Receptors, Immunologic/metabolism , Receptors, Immunologic/genetics , Glycolysis/physiology , Thyroid Hormone-Binding Proteins
20.
Pflugers Arch ; 476(9): 1353-1368, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38570355

ABSTRACT

Mammalian cells utilize glucose as a primary carbon source to produce energy for most cellular functions. However, the bioenergetic homeostasis of cells can be perturbed by environmental alterations, such as changes in oxygen levels which can be associated with bacterial infection. Reduction in oxygen availability leads to a state of hypoxia, inducing numerous cellular responses that aim to combat this stress. Importantly, hypoxia strongly augments cellular glycolysis in most cell types to compensate for the loss of aerobic respiration. Understanding how this host cell metabolic adaptation to hypoxia impacts the course of bacterial infection will identify new anti-microbial targets. This review will highlight developments in our understanding of glycolytic substrate channeling and spatiotemporal enzymatic organization in response to hypoxia, shedding light on the integral role of the hypoxia-inducible factor (HIF) during host-pathogen interactions. Furthermore, the ability of intracellular and extracellular bacteria (pathogens and commensals alike) to modulate host cellular glucose metabolism will be discussed.


Subject(s)
Glycolysis , Humans , Glycolysis/physiology , Animals , Adaptation, Physiological , Host-Pathogen Interactions , Hypoxia-Inducible Factor 1/metabolism
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