scholarly journals Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Xinde Zheng ◽  
Leah Boyer ◽  
Mingji Jin ◽  
Jerome Mertens ◽  
Yongsung Kim ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Neuronal Differentiation ◽  
Neural Progenitor Cells ◽  
Aerobic Glycolysis ◽  
Neuronal Cell Death ◽  
Constitutive Expression ◽  
Neuronal Cell ◽  
Metabolic Reprogramming ◽  
Kinase Gene ◽  
Protein Levels

How metabolism is reprogrammed during neuronal differentiation is unknown. We found that the loss of hexokinase (HK2) and lactate dehydrogenase (LDHA) expression, together with a switch in pyruvate kinase gene splicing from PKM2 to PKM1, marks the transition from aerobic glycolysis in neural progenitor cells (NPC) to neuronal oxidative phosphorylation. The protein levels of c-MYC and N-MYC, transcriptional activators of the HK2 and LDHA genes, decrease dramatically. Constitutive expression of HK2 and LDHA during differentiation leads to neuronal cell death, indicating that the shut-off aerobic glycolysis is essential for neuronal survival. The metabolic regulators PGC-1α and ERRγ increase significantly upon neuronal differentiation to sustain the transcription of metabolic and mitochondrial genes, whose levels are unchanged compared to NPCs, revealing distinct transcriptional regulation of metabolic genes in the proliferation and post-mitotic differentiation states. Mitochondrial mass increases proportionally with neuronal mass growth, indicating an unknown mechanism linking mitochondrial biogenesis to cell size.

scholarly journals Wild-Type and Mutant FUS Expression Reduce Proliferation and Neuronal Differentiation Properties of Neural Stem Progenitor Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7566
Author(s):  
Eleonora Stronati ◽  
Stefano Biagioni ◽  
Mario Fiore ◽  
Mauro Giorgi ◽  
Giancarlo Poiana ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nervous System Development ◽  
Mutant Form ◽  
Wild Type ◽  
Fused In Sarcoma ◽  
Glial Lineage

Nervous system development involves proliferation and cell specification of progenitor cells into neurons and glial cells. Unveiling how this complex process is orchestrated under physiological conditions and deciphering the molecular and cellular changes leading to neurological diseases is mandatory. To date, great efforts have been aimed at identifying gene mutations associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mutations in the RNA/DNA binding protein Fused in Sarcoma/Translocated in Liposarcoma (FUS/TLS) have been associated with motor neuron degeneration in rodents and humans. Furthermore, increased levels of the wild-type protein can promote neuronal cell death. Despite the well-established causal link between FUS mutations and ALS, its role in neural cells remains elusive. In order to shed new light on FUS functions we studied its role in the control of neural stem progenitor cell (NSPC) properties. Here, we report that human wild-type Fused in Sarcoma (WT FUS), exogenously expressed in mouse embryonic spinal cord-derived NSPCs, was localized in the nucleus, caused cell cycle arrest in G1 phase by affecting cell cycle regulator expression, and strongly reduced neuronal differentiation. Furthermore, the expression of the human mutant form of FUS (P525L-FUS), associated with early-onset ALS, drives the cells preferentially towards a glial lineage, strongly reducing the number of developing neurons. These results provide insight into the involvement of FUS in NSPC proliferation and differentiation into neurons and glia.

scholarly journals Integrin αvβ3 Engagement Regulates Glucose Metabolism and Migration through Focal Adhesion Kinase (FAK) and Protein Arginine Methyltransferase 5 (PRMT5) in Glioblastoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1111
Author(s):  
Pulin Che ◽  
Lei Yu ◽  
Gregory K. Friedman ◽  
Meimei Wang ◽  
Xiaoxue Ke ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Focal Adhesion ◽  
Aerobic Glycolysis ◽  
Integrin Αvβ3 ◽  
Metabolic Reprogramming ◽  
Migration And Invasion ◽  
Metabolic Shift ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Glioblastoma Cells ◽  
Arginine Methyltransferase

Metabolic reprogramming promotes glioblastoma cell migration and invasion. Integrin αvβ3 is one of the major integrin family members in glioblastoma multiforme cell surface mediating interactions with extracellular matrix proteins that are important for glioblastoma progression. The role of αvβ3 integrin in regulating metabolic reprogramming and its mechanism of action have not been determined in glioblastoma cells. Integrin αvβ3 engagement with osteopontin promotes glucose uptake and aerobic glycolysis, while inhibiting mitochondrial oxidative phosphorylation. Blocking or downregulation of integrin αvβ3 inhibits glucose uptake and aerobic glycolysis and promotes mitochondrial oxidative phosphorylation, resulting in decreased migration and growth in glioblastoma cells. Pharmacological inhibition of focal adhesion kinase (FAK) or downregulation of protein arginine methyltransferase 5 (PRMT5) blocks metabolic shift toward glycolysis and inhibits glioblastoma cell migration and invasion. These results support that integrin αvβ3 and osteopontin engagement plays an important role in promoting the metabolic shift toward glycolysis and inhibiting mitochondria oxidative phosphorylation in glioblastoma cells. The metabolic shift in cell energy metabolism is coupled to changes in migration, invasion, and growth, which are mediated by downstream FAK and PRMT5 in glioblastoma cells.

scholarly journals Insertion of the βGeo Promoter Trap into the Fem1c Gene of ROSA3 Mice

2004 ◽  
Vol 24 (9) ◽  
pp. 3794-3803 ◽  
Author(s):  
Cassandra L. Schlamp ◽  
Andrew T. Thliveris ◽  
Yan Li ◽  
Louis P. Kohl ◽  
Claudia Knop ◽  
...  
Keyword(s):  
Cell Death ◽  
Ganglion Cells ◽  
Neuronal Cell Death ◽  
Insertion Site ◽  
Neuronal Cell ◽  
Pyramidal Cells ◽  
Coding Region ◽  
Protein Levels ◽  
Molecular Events ◽  
Promoter Trap

ABSTRACT ROSA3 mice were developed by retroviral insertion of the βGeo gene trap vector. Adult ROSA3 mice exhibit widespread expression of the trap gene in epithelial cells found in most organs. In the central nervous system the highest expression of βGeo is found in CA1 pyramidal cells of the hippocampus, Purkinje cells of the cerebellum, and ganglion cells of the retina. Characterization of the genomic insertion site for βGeo in ROSA3 mice shows that the trap vector is located in the first intron of Fem1c, a gene homologous to the sex-determining gene fem-1 of Caenorhabditis elegans. Transcription of the Rosa3 allele (R3) yields a spliced message that includes the first exon of Fem1c and the βGeo coding region. Although normal processing of the Fem1c transcript is disrupted in homozygous Rosa3 (Fem1cR3/R3 ) mice, some tissues show low levels of a partially processed transcript containing exons 2 and 3. Since the entire coding region of Fem1c is located in these two exons, Fem1cR3/R3 mice may still be able to express a putative FEM1C protein. To this extent, Fem1cR3/R3 mice show no adverse effects in their sexual development or fertility or in the attenuation of neuronal cell death, another function that has been attributed to both fem-1 and a second mouse homolog, Fem1b. Examination of βGeo expression in ganglion cells after exposure to damaging stimuli indicates that protein levels are rapidly depleted prior to cell death, making the βGeo reporter gene a potentially useful marker to study early molecular events in damaged neurons.

scholarly journals TGF-β1 modifies histone acetylation and acetyl-coenzyme A metabolism in renal myofibroblasts

2019 ◽  
Vol 316 (3) ◽  
pp. F517-F529 ◽  
Author(s):  
Edward R. Smith ◽  
Belinda Wigg ◽  
Stephen G. Holt ◽  
Timothy D. Hewitson
Keyword(s):  
Histone Acetylation ◽  
Transforming Growth Factor ◽  
Aerobic Glycolysis ◽  
Transforming Growth Factor Β1 ◽  
Metabolic Reprogramming ◽  
Acetyl Coa ◽  
Hdac Activity ◽  
Protein Levels ◽  
H3 Acetylation ◽  
Tgf Β1

Histone acetylation is an important modulator of gene expression in fibrosis. This study examined the effect of the pre-eminent fibrogenic cytokine transforming growth factor-β1 (TGF-β1) on histone 3 (H3) acetylation and its regulatory kinetics in renal myofibroblasts. Fibroblasts propagated from rat kidneys after ureteric obstruction were treated with recombinant TGF-β1 or vehicle for 48 h. TGF-β1-induced myofibroblast activation was accompanied by a net decrease in total H3 acetylation, although changes in individual marks were variable. This was paralleled by a generalized reduction in histone acetyltransferases (HAT) and divergent changes in histone deacetylase (HDAC) enzymes at both transcript and protein levels. Globally, this was manifest in a reduction in total HAT activity and increase in HDAC activity. TGF-β1 induced a shift in cellular metabolism from oxidative respiration to aerobic glycolysis, resulting in reduced acetyl-CoA. The reduction in total H3 acetylation could be rescued by providing exogenous citrate or alternative sources of acetyl-CoA without ameliorating changes in HAT/HDAC activity. In conclusion, TGF-β1 produces a metabolic reprogramming in renal fibroblasts, with less H3 acetylation through reduced acetylation, increased deacetylation, and changes in carbon availability. Our results suggest that acetyl-CoA availability predominates over HAT and HDAC activity as a key determinant of H3 acetylation in response to TGF-β1.

scholarly journals Cerebral Ischemia Causes Dysregulation of Synaptic Adhesion in Mouse Synaptosomes

2007 ◽  
Vol 28 (1) ◽  
pp. 99-110 ◽  
Author(s):  
Willard J Costain ◽  
Ingrid Rasquinha ◽  
Jagdeep K Sandhu ◽  
Peter Rippstein ◽  
Bogdan Zurakowski ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Adhesion Molecules ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Synaptic Proteins ◽  
Mrna Levels ◽  
Neuronal Nuclei ◽  
Protein Levels

Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (< 48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (≈650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.

scholarly journals Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
René G. Feichtinger ◽  
Daniel Neureiter ◽  
Tom Skaria ◽  
Silja Wessler ◽  
Timothy L. Cover ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Complex I ◽  
Aerobic Glycolysis ◽  
Complex Iii ◽  
Complex Ii ◽  
Gastric Carcinomas ◽  
Cellular Energy ◽  
Protein Levels ◽  
Chemically Induced ◽  
Grade 3

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have toHelicobacter pyloriinfection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2021 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Young Min Oh ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

scholarly journals Calcium-dependent serine-threonine phosphatase, calcineurin inactivation mediated by baicalein attenuates prion protein-mediated neuronal cell damage

2020 ◽  
Author(s):  
Jeong-Min Hong ◽  
Ji-Hong Moon ◽  
Sang-Youel Park
Keyword(s):  
Cell Death ◽  
Prion Protein ◽  
Cell Damage ◽  
Prion Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Therapeutic Drug ◽  
Autophagic Flux ◽  
Calcium Dependent ◽  
Protein Levels

Abstract Background: Prion diseases are a group of unvaryingly fatal neurodegenerative disorders characterized by neuronal cell death. Calcineurin and autophagy mediate prion-induced neurodegeneration, suggesting that inhibition of calcineurin and autophagy could be a target for therapy. Baicalein has been reported to exert neuroprotective effects against calcium-dependent neuronal cell death. Results: In the present study, we investigated whether baicalein attenuates prion peptide-mediated neurotoxicity and reduces calcineurin. We found that baicalein treatment inhibits prion protein-induced apoptosis. Baicalein inhibited calcium up-regulation and protected the cells against prion peptide‑induced neuron cell death by calcineurin inactivation. Furthermore, baicalein increased p62 protein levels and decrease LC3-II protein levels indicating autophagic flux inhibition and baicalein inhibited prion protein-induced neurotoxicity through autophagy flux inhibition. Conclusions: Taken together, this study demonstrated that baicalein attenuated prion peptide-induced neurotoxicity via calcineurin inactivation and autophagic flux reduction, and also suggest that baicalein may be an effective therapeutic drug against neurodegenerative diseases, including prion diseases.

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