metabolic reprogramming
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Significance: The architecture of the mitochondrial network and cristae critically impact cell differentiation and identity. Cells undergoing metabolic reprogramming to aerobic glycolysis (Warburg effect), such as immune cells, stem cells, and cancer cells, go through controlled modifications in mitochondrial architecture, which is critical for achieving the resulting cellular phenotype. Recent Advances: Recent studies in immunometabolism have shown that the manipulation of mitochondrial network dynamics and cristae shape directly affects T cell phenotype and macrophage polarization through altering energy metabolism. Similar manipulations also alter the specific metabolic phenotypes that accompany somatic reprogramming, stem cell differentiation, and cancer cells. The modulation of oxidative phosphorylation activity, accompanied by changes in metabolite signaling, reactive oxygen species generation, and adenosine triphosphate levels, is the shared underlying mechanism. Critical Issues: The plasticity of mitochondrial architecture is particularly vital for metabolic reprogramming. Consequently, failure to adapt the appropriate mitochondrial morphology often compromises the differentiation and identity of the cell. Immune, stem, and tumor cells exhibit striking similarities in their coordination of mitochondrial morphology with metabolic pathways. However, although many general unifying principles can be observed, their validity is not absolute, and the mechanistic links thus need to be further explored. Future Directions: Better knowledge of the molecular mechanisms involved and their relationships to both mitochondrial network and cristae morphology will not only further deepen our understanding of energy metabolism but may also contribute to improved therapeutic manipulation of cell viability, differentiation, proliferation, and identity in many different cell types. Antioxid. Redox Signal. 39, 684-707.
Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPARγ agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPARγ protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells' metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPKα and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy.
- MeSH
- hypoglykemika * farmakologie MeSH
- lidé MeSH
- metabolické přeprogramování MeSH
- mitochondrie metabolismus účinky léků MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * metabolismus farmakoterapie patologie MeSH
- pioglitazon * farmakologie MeSH
- pohyb buněk účinky léků MeSH
- PPAR gama * agonisté metabolismus MeSH
- proliferace buněk účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Microbial-associated molecular patterns activate several MAP kinases, which are major regulators of the innate immune response in Arabidopsis thaliana that induce large-scale changes in gene expression. Here, we determine whether microbial-associated molecular pattern-triggered gene expression involves modifications at the chromatin level. RESULTS: Histone acetylation and deacetylation are major regulators of microbial-associated molecular pattern-triggered gene expression and implicate the histone deacetylase HD2B in the reprogramming of defence gene expression and innate immunity. The MAP kinase MPK3 directly interacts with and phosphorylates HD2B, thereby regulating the intra-nuclear compartmentalization and function of the histone deacetylase. CONCLUSIONS: By studying a number of gene loci that undergo microbial-associated molecular pattern-dependent activation or repression, our data reveal a mechanistic model for how protein kinase signaling directly impacts chromatin reprogramming in plant defense.
- MeSH
- Arabidopsis imunologie MeSH
- chromatin fyziologie MeSH
- flagelin imunologie MeSH
- fosforylace MeSH
- fyziologický stres MeSH
- histondeacetylasy metabolismus MeSH
- histony metabolismus MeSH
- imunita rostlin * MeSH
- mitogenem aktivované proteinkinasy kinas metabolismus MeSH
- přirozená imunita MeSH
- proteiny huseníčku metabolismus MeSH
- restrukturace chromatinu * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pozdní následky infekčních onemocnění, označované jako pozdní infekční syndrom, představují déletrvající a také výraznější zdravotní problémy, které se mohou vyskytnout po akutní virové, bakteriální nebo parazitární infekci. Jako jeden z klíčových konceptů pro pochopení těchto dlouhodobých efektů se jeví trénovaná imunita, spojená s funkčním přeprogramováním vrozených imunitních buněk prostřednictvím epigenetického a metabolického přepojení. Trvání trénovaných imunitních reakcí se liší v závislosti na povaze podnětu a intenzitě vyvolané imunitní odpovědi. Její nadměrná aktivace zvyšuje riziko autoinflamatorních a autoimunitních poruch, neurodegenerativních syndromů, aterosklerózy a kardiovaskulárních onemocnění, naproti tomu potlačení efektorových funkcí imunitních buněk vede k postinfekční imunitní paralýze.
The late consequences of infectious diseases, referred to as post-acute infection, represent longer-lasting and more pronounced health problems that can occur after an acute viral, bacterial or parasitic infection. A key concept for understanding these long-term effects appears to be trained immunity, associated with functional reprogramming of innate immune cells through epigenetic and metabolic rewiring. The duration of trained immune responses varies depending on the nature of the stimulus and the intensity of the immune response elicited. Its excessive activation increases the risk of autoinflammatory and autoimmune disorders, neurodegenerative syndromes, atherosclerosis and cardiovascular diseases, while suppression of the effector functions of immune cells leads to post-infectious immune paralysis.
- MeSH
- infekční nemoci * MeSH
- lidé MeSH
- metabolické přeprogramování MeSH
- trénovaná imunita * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Pulmonary hypertension is a complex disease of the pulmonary vasculature, which in severe cases terminates in right heart failure. Complex remodeling of pulmonary arteries comprises the central issue of its pathology. This includes extensive proliferation, apoptotic resistance and inflammation. As such, the molecular and cellular features of pulmonary hypertension resemble hallmark characteristics of cancer cell behavior. The vascular remodeling derives from significant metabolic changes in resident cells, which we describe in detail. It affects not only cells of pulmonary artery wall, but also its immediate microenvironment involving cells of immune system (i.e., macrophages). Thus aberrant metabolism constitutes principle component of the cancer-like theory of pulmonary hypertension. The metabolic changes in pulmonary artery cells resemble the cancer associated Warburg effect, involving incomplete glucose oxidation through aerobic glycolysis with depressed mitochondrial catabolism enabling the fueling of anabolic reactions with amino acids, nucleotides and lipids to sustain proliferation. Macrophages also undergo overlapping but distinct metabolic reprogramming inducing specific activation or polarization states that enable their participation in the vascular remodeling process. Such metabolic synergy drives chronic inflammation further contributing to remodeling. Enhanced glycolytic flux together with suppressed mitochondrial bioenergetics promotes the accumulation of reducing equivalents, NAD(P)H. We discuss the enzymes and reactions involved. The reducing equivalents modulate the regulation of proteins using NAD(P)H as the transcriptional co-repressor C-terminal binding protein 1 cofactor and significantly impact redox status (through GSH, NAD(P)H oxidases, etc.), which together act to control the phenotype of the cells of pulmonary arteries. The altered mitochondrial metabolism changes its redox poise, which together with enhanced NAD(P)H oxidase activity and reduced enzymatic antioxidant activity promotes a pro-oxidative cellular status. Herein we discuss all described metabolic changes along with resultant alterations in redox status, which result in excessive proliferation, apoptotic resistance, and inflammation, further leading to pulmonary arterial wall remodeling and thus establishing pulmonary artery hypertension pathology.
- MeSH
- arteria pulmonalis metabolismus patofyziologie MeSH
- energetický metabolismus * MeSH
- glykolýza MeSH
- lidé MeSH
- makrofágy metabolismus MeSH
- mitochondrie metabolismus MeSH
- oxidace-redukce MeSH
- plicní hypertenze metabolismus patofyziologie MeSH
- remodelace cév MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.
- MeSH
- buněčné dýchání MeSH
- chronická nemoc MeSH
- citrátový cyklus MeSH
- down regulace MeSH
- energetický metabolismus MeSH
- fenotyp MeSH
- fibroblasty metabolismus MeSH
- glykolýza MeSH
- hypoxie komplikace patologie MeSH
- kyselina pyrohroznová metabolismus MeSH
- lidé MeSH
- makrofágy metabolismus MeSH
- mitochondrie metabolismus MeSH
- oxidace-redukce MeSH
- oxidativní fosforylace MeSH
- parakrinní signalizace MeSH
- plíce patologie MeSH
- plicní hypertenze komplikace metabolismus patologie MeSH
- přeprogramování buněk * MeSH
- pyruvátdehydrogenasový komplex metabolismus MeSH
- respirační komplex I metabolismus MeSH
- skot MeSH
- superoxidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
SIGNIFICANCE: The molecular events that promote the development of pulmonary hypertension (PH) are complex and incompletely understood. The complex interplay between the pulmonary vasculature and its immediate microenvironment involving cells of immune system (i.e., macrophages) promotes a persistent inflammatory state, pathological angiogenesis, and fibrosis that are driven by metabolic reprogramming of mesenchymal and immune cells. Recent Advancements: Consistent with previous findings in the field of cancer metabolism, increased glycolytic rates, incomplete glucose and glutamine oxidation to support anabolism and anaplerosis, altered lipid synthesis/oxidation ratios, increased one-carbon metabolism, and activation of the pentose phosphate pathway to support nucleoside synthesis are but some of the key metabolic signatures of vascular cells in PH. In addition, metabolic reprogramming of macrophages is observed in PH and is characterized by distinct features, such as the induction of specific activation or polarization states that enable their participation in the vascular remodeling process. CRITICAL ISSUES: Accumulation of reducing equivalents, such as NAD(P)H in PH cells, also contributes to their altered phenotype both directly and indirectly by regulating the activity of the transcriptional co-repressor C-terminal-binding protein 1 to control the proliferative/inflammatory gene expression in resident and immune cells. Further, similar to the role of anomalous metabolism in mitochondria in cancer, in PH short-term hypoxia-dependent and long-term hypoxia-independent alterations of mitochondrial activity, in the absence of genetic mutation of key mitochondrial enzymes, have been observed and explored as potential therapeutic targets. FUTURE DIRECTIONS: For the foreseeable future, short- and long-term metabolic reprogramming will become a candidate druggable target in the treatment of PH. Antioxid. Redox Signal. 28, 230-250.
- MeSH
- energetický metabolismus MeSH
- epigeneze genetická MeSH
- glukosa-6-fosfátdehydrogenasa metabolismus MeSH
- glukosa metabolismus MeSH
- glykolýza MeSH
- hypoxie metabolismus MeSH
- izoenzymy metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- makrofágy MeSH
- mitochondrie metabolismus MeSH
- oxidace-redukce MeSH
- pentózofosfátový cyklus MeSH
- plicní hypertenze etiologie metabolismus MeSH
- regulace genové exprese MeSH
- superoxidy metabolismus MeSH
- uhlík metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer.
- Publikační typ
- časopisecké články MeSH
- přehledy 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.
- Klíčová slova
- p53, lýtransketoláza, glyoxaláza, metabolizmus,
- MeSH
- aerobióza MeSH
- diabetes mellitus 2. typu * komplikace MeSH
- glukosa metabolismus MeSH
- glykolýza fyziologie MeSH
- hypoglykemika škodlivé účinky MeSH
- lidé MeSH
- metabolické sítě a dráhy fyziologie MeSH
- metformin farmakologie škodlivé účinky terapeutické užití MeSH
- nádorová transformace buněk * metabolismus MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory * metabolismus MeSH
- obezita MeSH
- proliferace buněk MeSH
- transketolasa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.
