Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.
- MeSH
- Energy Metabolism * physiology MeSH
- Humans MeSH
- Metabolic Networks and Pathways * physiology MeSH
- Brain * metabolism MeSH
- Nerve Net * metabolism MeSH
- Neurons * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- MeSH
- Obesity, Abdominal physiopathology MeSH
- Adipokines physiology classification metabolism MeSH
- Hyperglycemia physiopathology MeSH
- Hypertension physiopathology MeSH
- Insulin Resistance physiology MeSH
- Humans MeSH
- Metabolic Networks and Pathways physiology MeSH
- Metabolic Syndrome * genetics physiopathology MeSH
- Microbiota physiology MeSH
- Overnutrition physiopathology MeSH
- Neurotransmitter Agents classification metabolism MeSH
- Oxidative Stress physiology MeSH
- Renin-Angiotensin System physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: The Werner syndrome protein (WRN) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by WRN depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation. RESULTS: To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after WRN knockdown. We determined that WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1). CONCLUSIONS: Our findings suggest that WRN influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of WRN, which is especially important for the proliferation of cancer cells.
- MeSH
- Cell Nucleus metabolism MeSH
- HeLa Cells MeSH
- RecQ Helicases genetics MeSH
- Werner Syndrome Helicase metabolism MeSH
- Humans MeSH
- RNA, Messenger genetics MeSH
- Metabolic Networks and Pathways physiology MeSH
- Cell Line, Tumor MeSH
- Neoplasms metabolism MeSH
- Oxidation-Reduction MeSH
- RNA Processing, Post-Transcriptional physiology MeSH
- Cell Proliferation physiology MeSH
- RNA-Binding Proteins metabolism MeSH
- RNA Transport physiology MeSH
- Werner Syndrome metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Malfunction of the circadian timing system may result in cardiovascular and metabolic diseases, and conversely, these diseases can impair the circadian system. The aim of this study was to reveal whether the functional state of the circadian system of spontaneously hypertensive rats (SHR) differs from that of control Wistar rat. This study is the first to analyze the function of the circadian system of SHR in its complexity, i.e., of the central clock in the suprachiasmatic nuclei (SCN) as well as of the peripheral clocks. The functional properties of the SCN clock were estimated by behavioral output rhythm in locomotor activity and daily profiles of clock gene expression in the SCN determined by in situ hybridization. The function of the peripheral clocks was assessed by daily profiles of clock gene expression in the liver and colon by RT-PCR and in vitro using real time recording of Bmal1-dLuc reporter. The potential impact of the SHR phenotype on circadian control of the metabolic pathways was estimated by daily profiles of metabolism-relevant gene expression in the liver and colon. The results revealed that SHR exhibited an early chronotype, because the central SCN clock was phase advanced relative to light/dark cycle and the SCN driven output rhythm ran faster compared to Wistar rats. Moreover, the output rhythm was dampened. The SHR peripheral clock reacted to the dampened SCN output with tissue-specific consequences. In the colon of SHR the clock function was severely altered, whereas the differences are only marginal in the liver. These changes may likely result in a mutual desynchrony of circadian oscillators within the circadian system of SHR, thereby potentially contributing to metabolic pathology of the strain. The SHR may thus serve as a valuable model of human circadian disorders originating in poor synchrony of the circadian system with external light/dark regime.
- MeSH
- Time Factors MeSH
- Circadian Clocks * MeSH
- Species Specificity MeSH
- Phenotype MeSH
- Fibroblasts metabolism MeSH
- Liver metabolism physiopathology MeSH
- Colon metabolism physiopathology MeSH
- Rats MeSH
- Metabolic Networks and Pathways physiology MeSH
- Suprachiasmatic Nucleus metabolism physiopathology MeSH
- Organ Specificity MeSH
- Motor Activity physiology MeSH
- Rats, Inbred SHR MeSH
- Transcriptome MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Převažující aerobní glykolýza v nádorových buňkách (tzv. Warburgův efekt) je na základě současných poznatků důsledkem přeprogramování buněčného metabolizmu během procesu maligní transformace. Regulace metabolizmu je neoddělitelnou komponentou procesu buněčné proliferace a je těsně svázána s aktivitami onkogenů a supresorových genů. Smyslem metabolické transformace nádorových buněk (a rovněž normálních intenzivně proliferujících buněk) je inkorporovat větší podíl metabolitů glukózy do nově syntetizovaných makromolekul. Mimo to aerobní glykolýza poskytuje nádorovým buňkám několik dalších selektivních výhod. Epidemiologická data naznačují, že diabetes mellitus 2. typu je asociován s rostoucí incidencí několika typů nádorů a že mortalita v důsledku nádorových onemocnění může být ovlivněna léčbou určitými druhy antidiabetik, nicméně další výzkum je nutný k vysvětlení toho, zda je tento vztah kauzální. Hlubší pochopení metabolizmu rychle proliferujících buněk může vést k dalšímu zlepšení protinádorové, imunosupresivní a protizánětové léčby.
The prevailing aerobic glycolysis (so called Warburg effect) in cancer cells is according to current understanding the consequence of reprogramming of cellular metabolism during the process of malignant transformation. Metabolic regulation is inseparable component of cell proliferation machinery and has a tight link with activities of oncogenes and suppressor genes. The purpose of metabolic reprogramming of cancer (but also normal intensively proliferating cells) is to incorporate greater fraction of glucose metabolites into newly synthesised macromolecules. Apart from that, aerobic glycolysis confers several other selective advantages to cancer cells. Epidemiological data indicate that type 2 diabetes mellitus is associated with increased incidence of several types of cancer and that cancer mortality can be influenced by certain types of anti-diabetic treatment, however future research is needed to explain whether this relationship might be causal. Deeper knowledge about metabolic properties of rapidly proliferating cells can be exploited for further improvement of anti-cancer, immunosuppressive or anti-inflammatory therapies.
- Keywords
- p53, lýtransketoláza, glyoxaláza, metabolizmus,
- MeSH
- Aerobiosis MeSH
- Diabetes Mellitus, Type 2 * complications MeSH
- Glucose metabolism MeSH
- Glycolysis physiology MeSH
- Hypoglycemic Agents adverse effects MeSH
- Humans MeSH
- Metabolic Networks and Pathways physiology MeSH
- Metformin pharmacology adverse effects therapeutic use MeSH
- Cell Transformation, Neoplastic * metabolism MeSH
- Tumor Suppressor Protein p53 metabolism MeSH
- Neoplasms * metabolism MeSH
- Obesity MeSH
- Cell Proliferation MeSH
- Transketolase MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
We posit the following hypothesis: Independently of whether malignant tumors are initiated by a fundamental reprogramming of gene expression or seeded by stem cells, "waves" of gene expression that promote metabolic changes occur during carcinogenesis, beginning with oncogene-mediated changes, followed by hypoxia-induced factor (HIF)-mediated gene expression, both resulting in the highly glycolytic "Warburg" phenotype and suppression of mitochondrial biogenesis. Because high proliferation rates in malignancies cause aglycemia and nutrient shortage, the third (second oncogene) "wave" of adaptation stimulates glutaminolysis, which in certain cases partially re-establishes oxidative phosphorylation; this involves the LKB1-AMPK-p53, PI3K-Akt-mTOR axes and MYC dysregulation. Oxidative glutaminolysis serves as an alternative pathway compensating for cellular ATP. Together with anoxic glutaminolysis it provides pyruvate, lactate, and the NADPH pool (alternatively to pentose phosphate pathway). Retrograde signaling from revitalized mitochondria might constitute the fourth "wave" of gene reprogramming. In turn, upon reversal of the two Krebs cycle enzymes, glutaminolysis may partially (transiently) function even during anoxia, thereby further promoting malignancy. The history of the carcinogenic process within each malignant tumor determines the final metabolic phenotype of the selected surviving cells, resulting in distinct cancer bioenergetic phenotypes ranging from the highly glycolytic "classic Warburg" to partial or enhanced oxidative phosphorylation. We discuss the bioenergetically relevant functions of oncogenes, the involvement of mitochondrial biogenesis/degradation in carcinogenesis, the yet unexplained Crabtree effect of instant glucose blockade of respiration, and metabolic signaling stemming from the accumulation of succinate, fumarate, pyruvate, lactate, and oxoglutarate by interfering with prolyl hydroxylase domain enzyme-mediated hydroxylation of HIFα prolines.
- MeSH
- Phosphatidylinositol 3-Kinase metabolism MeSH
- Adaptation, Biological physiology MeSH
- Energy Metabolism physiology MeSH
- Genes, myc physiology MeSH
- Glucose metabolism MeSH
- Glutamine metabolism MeSH
- Cell Hypoxia MeSH
- Lactic Acid metabolism MeSH
- Pyruvic Acid metabolism MeSH
- Humans MeSH
- Metabolic Networks and Pathways physiology MeSH
- Mitochondria metabolism MeSH
- Neoplasms metabolism MeSH
- Oxidative Phosphorylation MeSH
- Cell Proliferation MeSH
- Protein Serine-Threonine Kinases metabolism MeSH
- Gene Expression Regulation physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.
- MeSH
- Excitatory Amino Acid Agonists pharmacology MeSH
- Aldehydes metabolism MeSH
- Time Factors MeSH
- Down-Regulation drug effects physiology MeSH
- Energy Metabolism drug effects physiology MeSH
- Epilepsy metabolism physiopathology MeSH
- Homocysteine analogs & derivatives toxicity MeSH
- Convulsants toxicity MeSH
- Rats MeSH
- Metabolic Networks and Pathways physiology MeSH
- Survival Rate MeSH
- Mitochondrial Diseases chemically induced metabolism physiopathology MeSH
- Mitochondria drug effects metabolism MeSH
- Disease Models, Animal MeSH
- Cerebral Cortex metabolism pathology physiopathology MeSH
- Animals, Newborn MeSH
- Oxidative Stress drug effects physiology MeSH
- Rats, Wistar MeSH
- Electron Transport Complex I drug effects metabolism MeSH
- Free Radical Scavengers pharmacology MeSH
- Tyrosine analogs & derivatives metabolism MeSH
- Seizures chemically induced metabolism physiopathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Models, Biological MeSH
- Diabetes Mellitus, Type 1 complications blood metabolism MeSH
- Diabetes Mellitus, Type 2 complications blood metabolism MeSH
- Cardiovascular Diseases etiology blood metabolism MeSH
- Diabetes Complications metabolism prevention & control MeSH
- Blood Glucose metabolism MeSH
- Humans MeSH
- Metabolic Networks and Pathways physiology MeSH
- Oxidative Stress physiology MeSH
- Glycation End Products, Advanced physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Overall MeSH
- MeSH
- Chromatography, Liquid methods utilization MeSH
- Chromatography, Gas methods utilization MeSH
- Endocrinology methods standards statistics & numerical data MeSH
- Financing, Organized MeSH
- Metabolic Networks and Pathways physiology drug effects MeSH
- Least-Squares Analysis MeSH
- Regression Analysis MeSH
- Software MeSH
- Statistics as Topic methods MeSH
- Pregnancy MeSH
- Check Tag
- Pregnancy MeSH
