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Autophagy Dec 2023Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes....
Lactate is a glycolysis product that is produced from pyruvate by LDH (lactate dehydrogenase) and plays an important role in physiological and pathological processes. However, whether lactate regulates autophagy is still unknown. We recently reported that LDHA is phosphorylated at serine 196 by ULK1 (unc-51 like kinase 1) under nutrient-deprivation conditions, promoting lactate production. Then, lactate mediates PIK3C3/VPS34 lactylation at lysine 356 and lysine 781 via acyltransferase KAT5/TIP60. PIK3C3/VPS34 lactylation enhances the association of PIK3C3/VPS34 with BECN1 (beclin 1, autophagy related), ATG14 and UVRAG, increases PIK3C3/VPS34 lipid kinase activity, promotes macroautophagy/autophagy and facilitates the endolysosomal degradation pathway. PIK3C3/VPS34 hyperlactylation induces autophagy and plays an essential role in skeletal muscle homeostasis and cancer progression. Overall, this study describes an autophagy regulation mechanism and the integration of two highly conserved life processes: glycolysis and autophagy.
Topics: Autophagy; Autophagy-Related Proteins; Lactic Acid; Lysine; Beclin-1; Class III Phosphatidylinositol 3-Kinases; Glycolysis
PubMed: 37565742
DOI: 10.1080/15548627.2023.2246356 -
International Journal of Molecular... Aug 2023Neural tissue requires a great metabolic demand despite negligible intrinsic energy stores. As a result, the central nervous system (CNS) depends upon a continuous... (Review)
Review
Neural tissue requires a great metabolic demand despite negligible intrinsic energy stores. As a result, the central nervous system (CNS) depends upon a continuous influx of metabolic substrates from the blood. Disruption of this process can lead to impairment of neurological functions, loss of consciousness, and coma within minutes. Intricate neurovascular networks permit both spatially and temporally appropriate metabolic substrate delivery. Lactate is the end product of anaerobic or aerobic glycolysis, converted from pyruvate by lactate dehydrogenase-5 (LDH-5). Although abundant in the brain, it was traditionally considered a byproduct or waste of glycolysis. However, recent evidence indicates lactate may be an important energy source as well as a metabolic signaling molecule for the brain and astrocytes-the most abundant glial cell-playing a crucial role in energy delivery, storage, production, and utilization. The astrocyte-neuron lactate-shuttle hypothesis states that lactate, once released into the extracellular space by astrocytes, can be up-taken and metabolized by neurons. This review focuses on this hypothesis, highlighting lactate's emerging role in the brain, with particular emphasis on its role during development, synaptic plasticity, angiogenesis, and disease.
Topics: Humans; Neurodegenerative Diseases; Signal Transduction; Neuronal Plasticity; Brain; Lactic Acid
PubMed: 37686202
DOI: 10.3390/ijms241713398 -
Signal Transduction and Targeted Therapy Aug 2023Reprogrammed cellular metabolism is essential for maintaining cancer stem cells (CSCs) state. Here, we report that mitochondrial D-lactate catabolism is a necessary...
Reprogrammed cellular metabolism is essential for maintaining cancer stem cells (CSCs) state. Here, we report that mitochondrial D-lactate catabolism is a necessary initiating oncogenic event during tumorigenesis of esophageal squamous cell carcinoma (ESCC). We discover that cyclin-dependent kinase 7 (CDK7) phosphorylates nuclear Yes-associated protein 1 (YAP) at S127 and S397 sites and enhances its transcription function, which promotes D-lactate dehydrogenase (LDHD) protein expression. Moreover, LDHD is enriched significantly in ESCC-CSCs rather than differentiated tumor cells and high LDHD status is connected with poor prognosis in ESCC patients. Mechanistically, the CDK7-YAP-LDHD axis helps ESCC-CSCs escape from ferroptosis induced by D-lactate and generates pyruvate to satisfy energetic demands for their elevated self-renewal potential. Hence, we conclude that esophageal CSCs adopt a D-lactate elimination and pyruvate accumulation mode dependent on CDK7-YAP-LDHD axis, which drives stemness-associated hallmarks of ESCC-CSCs. Reasonably, targeting metabolic checkpoints may serve as an effective strategy for ESCC therapy.
Topics: Humans; Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Cyclin-Dependent Kinases; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Ferroptosis; L-Lactate Dehydrogenase; Lactic Acid; Neoplastic Stem Cells; Transcription Factors
PubMed: 37582812
DOI: 10.1038/s41392-023-01555-9 -
Drugs Dec 2023Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for... (Review)
Review
Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for the treatment of primary hyperoxaluria (PH). It reduces oxalate overproduction by inhibiting the expression of the hepatic lactate dehydrogenase (LDH) enzyme. Nedosiran received its first approval on 29 September 2023 in the USA to lower urinary oxalate levels in children aged ≥ 9 years and adults with PH type 1 (PH1) and relatively preserved kidney function [e.g. estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m]. This article summarizes the milestones in the development of nedosiran leading to this first approval for PH1.
Topics: Child; Adult; Humans; Hyperoxaluria, Primary; Oxalates; Lactate Dehydrogenases; RNA, Small Interfering
PubMed: 38060091
DOI: 10.1007/s40265-023-01976-4 -
Renal Failure Dec 2023The mortality rate of patients with sepsis-associated acute kidney injury (SA-AKI) in the intensive care unit (ICU) is high, and there is a need for early identification...
The association between lactate dehydrogenase to serum albumin ratio and the 28-day mortality in patients with sepsis-associated acute kidney injury in intensive care: a retrospective cohort study.
BACKGROUND
The mortality rate of patients with sepsis-associated acute kidney injury (SA-AKI) in the intensive care unit (ICU) is high, and there is a need for early identification of SA-AKI patients with poor prognoses. This study investigated the relationship between the lactate dehydrogenase to serum albumin ratio (LAR) and prognosis in patients with SA-AKI.
METHODS
We performed a retrospective cohort study of patients with SA-AKI who are represented in the Medical Information Mart for Intensive Care IV (MIMIC-IV). We used multivariable Cox regression analysis to determine adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analysis, survival curves, and curve fitting were used to evaluate a connection between the LAR and prognosis in patients with SA-AKI.
RESULTS
There were a total of 6453 participants in this research. The average age of the participants was 63.9 ± 16.1 years, and the average LAR was 11.0 (7.6, 17.7)/IU/g. After controlling for variables, the HRs for 28-day mortality were 1.20 (HR: 1.20, 95% CI: 1.05-1.38, ) and 1.61 (HR: 1.61, 95% CI: 1.41-1.84, ) for Tertile 2 (T2, 8.59≤ LAR< 14.66) and Tertile 3 (T3, LAR ≥ 14.66), respectively, compared to Tertile 1 (T1, LAR < 8.59). The outcomes for 90-day mortality and in-hospital death rate were comparable. The Kaplan-Meier (KM) analysis revealed that the group with greater LAR had higher 28-day and 90-day death rates.
CONCLUSION
Our study shows that LAR is associated with poor prognosis in patients with SA-AKI. Higher LAR is associated with higher 28-day, 90-day, and in-hospital mortality.
Topics: Humans; Middle Aged; Aged; Aged, 80 and over; Retrospective Studies; Hospital Mortality; Serum Albumin; L-Lactate Dehydrogenase; Critical Care; Acute Kidney Injury; Intensive Care Units; Prognosis; Sepsis
PubMed: 37194715
DOI: 10.1080/0886022X.2023.2212080 -
Cancer Letters Jul 2023Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and hypovascular tumor microenvironment. Nucleolar and spindle associated protein 1 (NUSAP1) is a...
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and hypovascular tumor microenvironment. Nucleolar and spindle associated protein 1 (NUSAP1) is a microtubule-associated protein that is known to be involved in cancer biology. Our study aimed to investigate the role of NUSAP1 in glycolytic metabolism and metastasis in PDAC. Expression and prognostic value of NUSAP1 in PDAC and common gastrointestinal tumors was evaluated. The function of NUSAP1 in PDAC progression was clarified by single-cell RNA-seq and further experiments in vitro, xenograft mouse model, spontaneous PDAC mice model and human tissue microarray. The downstream genes and signaling pathways regulated by NUSAP1 were explored by RNA-Seq. And the regulation of NUSAP1 on Lactate dehydrogenase A (LDHA)-mediated glycolysis and its underlying mechanism was further clarified by CHIP-seq. NUSAP1 was an independent unfavorable predictor of PDAC prognosis that playing a critical role in metastasis of PDAC by regulating LDHA-mediated glycolysis. Mechanically, NUSAP1 could bind to c-Myc and HIF-1α that forming a transcription regulatory complex localized to LDHA promoter region and enhanced its expression. Intriguingly, lactate upregulated NUSAP1 expression by inhibiting NUSAP1 protein degradation through lysine lactylated (Kla) modification, thus forming a NUSAP1-LDHA-glycolysis-lactate feedforward loop. The NUSAP1-LDHA-glycolysis-lactate feedforward loop is one of the underlying mechanisms to explain the metastasis and glycolytic metabolic potential in PDAC, which also provides a novel insights to understand the Warburg effect in cancer. Targeting NUSAP1 would be an attractive paradigm for PDAC treatment.
Topics: Humans; Animals; Mice; Lactate Dehydrogenase 5; Cell Line, Tumor; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Microtubule-Associated Proteins; Glycolysis; Lactates; Gene Expression Regulation, Neoplastic; L-Lactate Dehydrogenase; Cell Proliferation; Tumor Microenvironment
PubMed: 37354982
DOI: 10.1016/j.canlet.2023.216285 -
Nature Communications Mar 2024Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we...
Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
Topics: Animals; Humans; Mice; Glioblastoma; L-Lactate Dehydrogenase; Lactate Dehydrogenase 5; Lactic Acid; Symbiosis; Tumor Microenvironment
PubMed: 38443336
DOI: 10.1038/s41467-024-46193-z -
Hepatology (Baltimore, Md.) Mar 2024Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical...
BACKGROUND AND AIMS
Aerobic glycolysis reprogramming occurs during HSC activation, but how it is initiated and sustained remains unknown. We investigated the mechanisms by which canonical Wnt signaling regulated HSC glycolysis and the therapeutic implication for liver fibrosis.
APPROACH AND RESULTS
Glycolysis was examined in HSC-LX2 cells upon manipulation of Wnt/β-catenin signaling. Nuclear translocation of lactate dehydrogenase A (LDH-A) and its interaction with hypoxia-inducible factor-1α (HIF-1α) were investigated using molecular simulation and site-directed mutation assays. The pharmacological relevance of molecular discoveries was intensified in primary cultures, rodent models, and human samples. HSC glycolysis was enhanced by Wnt3a but reduced by β-catenin inhibitor or small interfering RNA (siRNA). Wnt3a-induced rapid transactivation and high expression of LDH-A dependent on TCF4. Wnt/β-catenin signaling also stimulated LDH-A nuclear translocation through importin β2 interplay with a noncanonical nuclear location signal of LDH-A. Mechanically, LDH-A bound to HIF-1α and enhanced its stability by obstructing hydroxylation-mediated proteasome degradation, leading to increased transactivation of glycolytic genes. The Gly28 residue of LDH-A was identified to be responsible for the formation of the LDH-A/HIF-1α transcription complex and stabilization of HIF-1α. Furthermore, LDH-A-mediated glycolysis was required for HSC activation in the presence of Wnt3a. Results in vivo showed that HSC activation and liver fibrosis were alleviated by HSC-specific knockdown of LDH-A in mice. β-catenin inhibitor XAV-939 mitigated HSC activation and liver fibrosis, which were abrogated by HSC-specific LDH-A overexpression in mice with fibrosis.
CONCLUSIONS
Inhibition of HSC glycolysis by targeting Wnt/β-catenin signaling and LDH-A had therapeutic promise for liver fibrosis.
Topics: Animals; Humans; Mice; beta Catenin; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Lactate Dehydrogenase 5; Liver Cirrhosis; Wnt Signaling Pathway; Hepatic Stellate Cells
PubMed: 37733267
DOI: 10.1097/HEP.0000000000000569