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.
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
- Pulmonary Artery metabolism physiopathology MeSH
- Energy Metabolism * MeSH
- Glycolysis MeSH
- Humans MeSH
- Macrophages metabolism MeSH
- Mitochondria metabolism MeSH
- Oxidation-Reduction MeSH
- Hypertension, Pulmonary metabolism physiopathology MeSH
- Vascular Remodeling MeSH
- Signal Transduction * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. 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
- Energy Metabolism MeSH
- Epigenesis, Genetic MeSH
- Glucosephosphate Dehydrogenase metabolism MeSH
- Glucose metabolism MeSH
- Glycolysis MeSH
- Hypoxia metabolism MeSH
- Isoenzymes metabolism MeSH
- Hydrogen-Ion Concentration MeSH
- Humans MeSH
- Macrophages MeSH
- Mitochondria metabolism MeSH
- Oxidation-Reduction MeSH
- Pentose Phosphate Pathway MeSH
- Hypertension, Pulmonary etiology metabolism MeSH
- Gene Expression Regulation MeSH
- Superoxides metabolism MeSH
- Carbon metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review 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.
- Publication type
- Journal Article MeSH
- Review MeSH
Východiska: Společným rysem metabolizmu nádorových buněk je schopnost získávat potřebné živiny z poměrně chudého prostředí a využívat je k udržení životaschopnosti a tvorbě nové biomasy. Změny v intracelulárních a extracelulárních metabolitech, které doprovází metabolické přeprogramování spojené s růstem nádoru, mají následně zásadní účinek na genovou expresi, buněčnou diferenciaci a mikroprostředí nádoru. V průběhu kancerogeneze čelí nádorové buňky selekčním tlakům, které je nutí neustále optimalizovat dominantní metabolické dráhy a nádorové buňky tak procházejí zásadními metabolickými reorganizacemi. Obecně platí, že vyšší flexibilita metabolických drah zvyšuje schopnost nádorových buněk sladit metabolické potřeby s měnícím se prostředím. Cíl: V tomto přehledovém článku pojednáváme o metabolických vlastnostech nádorových buněk a popisujeme účinek transformovaného metabolizmu na progresi nádoru. Domníváme se, že metabolické změny jsou pro rozvoj nádorů zásadní a mohly by poskytnout zajímavé cíle pro léčbu.
Background: A general characteristic of cancer metabolism is the skill to gain the essential nutrients from a relatively poor environment and use them effectively to maintain viability and create new biomass. The changes in intracellular and extracellular metabolites that accompany metabolic reprogramming associated with tumor growth subsequently affect gene expression, cell differentiation, and tumor microenvironment. During carcinogenesis, cancer cells face huge selection pressures that force them to constantly optimize dominant metabolic pathways and undergo major metabolic reorganizations. In general, greater flexibility of metabolic pathways increases the ability of tumor cells to satisfy their metabolic needs in a changing environment. Purpose: In this review, we discuss the metabolic properties of cancer cells and describe the tumor promoting effect of the transformed metabolism. We assume that changes in metabolism are significant enough to facilitate tumorigenesis and may provide interesting targets for cancer therapy.
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.
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 immunology MeSH
- Chromatin physiology MeSH
- Flagellin immunology MeSH
- Phosphorylation MeSH
- Stress, Physiological MeSH
- Histone Deacetylases metabolism MeSH
- Histones metabolism MeSH
- Plant Immunity * MeSH
- Mitogen-Activated Protein Kinase Kinases metabolism MeSH
- Immunity, Innate MeSH
- Arabidopsis Proteins metabolism MeSH
- Chromatin Assembly and Disassembly * MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Cell Respiration MeSH
- Chronic Disease MeSH
- Citric Acid Cycle MeSH
- Down-Regulation MeSH
- Energy Metabolism MeSH
- Phenotype MeSH
- Fibroblasts metabolism MeSH
- Glycolysis MeSH
- Hypoxia complications pathology MeSH
- Pyruvic Acid metabolism MeSH
- Humans MeSH
- Macrophages metabolism MeSH
- Mitochondria metabolism MeSH
- Oxidation-Reduction MeSH
- Oxidative Phosphorylation MeSH
- Paracrine Communication MeSH
- Lung pathology MeSH
- Hypertension, Pulmonary complications metabolism pathology MeSH
- Cellular Reprogramming * MeSH
- Pyruvate Dehydrogenase Complex metabolism MeSH
- Electron Transport Complex I metabolism MeSH
- Cattle MeSH
- Superoxides metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects of CA9-silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels of let-7 (lethal-7) family members. Simultaneously with the increase of let-7 miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28/let-7 axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis.
- MeSH
- Antigens, Neoplasm genetics MeSH
- Glycolysis MeSH
- Cell Hypoxia MeSH
- Carbonic Anhydrase IX genetics MeSH
- Hydrogen-Ion Concentration MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- MicroRNAs genetics MeSH
- Cell Line, Tumor MeSH
- Neoplastic Stem Cells metabolism MeSH
- Breast Neoplasms genetics metabolism MeSH
- Cellular Reprogramming MeSH
- RNA-Binding Proteins genetics MeSH
- Gene Expression Profiling MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Platelets are known to enhance the wound-healing activity of mesenchymal stem cells (MSCs). However, the mechanism by which platelets improve the therapeutic potential of MSCs has not been elucidated. Here, we provide evidence that, upon their activation, platelets transfer respiratory-competent mitochondria to MSCs primarily via dynamin-dependent clathrin-mediated endocytosis. We found that this process enhances the therapeutic efficacy of MSCs following their engraftment in several mouse models of tissue injury, including full-thickness cutaneous wound and dystrophic skeletal muscle. By combining in vitro and in vivo experiments, we demonstrate that platelet-derived mitochondria promote the pro-angiogenic activity of MSCs via their metabolic remodeling. Notably, we show that activation of the de novo fatty acid synthesis pathway is required for increased secretion of pro-angiogenic factors by platelet-preconditioned MSCs. These results reveal a new mechanism by which platelets potentiate MSC properties and underline the importance of testing platelet mitochondria quality prior to their clinical use.
- MeSH
- Wound Healing MeSH
- Mesenchymal Stem Cells metabolism MeSH
- Mitochondria metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Blood Platelets metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
