Search Results (64)

Metabolic flexibility describes the capability to switch between oxidative fuels depending on their availability during diet or exercise. In a previous study, we demonstrated that in response to training, marathon (DUhTP) mice, paternally selected for high treadmill performance, are metabolically more flexible than unselected control (DUC) mice. Since exercise-associated metabolic flexibility can be assessed by indirect calorimetry or partially by circulating lactate concentrations, we investigated these parameters in DUhTP and DUC mice. Therefore, males of both lines completed a three-week high-speed treadmill training or were physically inactive (sedentary) before being placed in a metabolic cage for three days (one day of acclimatization, two days with monitoring), measuring CO₂ and O₂ to calculate respiratory quotient (RQ) and fatty acid oxidation (FATox). Circulating blood lactate concentrations were determined. Training resulted in a lower RQ in DUhTP and an increased RQ in DUC mice compared to their sedentary counterparts. Increased FATox rates and lower lactate concentrations were observed in exercised DUhTP but not in DUC mice, indicating a shift to oxidative metabolism in DUhTP and a glycolytic one in DUC mice. Therefore, improved metabolic flexibility in DUhTP mice is verifiable up to three days after training. Full article

Despite the countless therapeutic advances achieved over the years, non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. To this primacy contribute both non-oncogene addicted and advanced NSCLCs, in which conventional therapies are only partially effective. The adiponectin receptor agonist AdipoRon has revealed antiproliferative action in different cancers, including osteosarcoma and pancreatic cancer. Herein, we investigated its potential anticancer role in NSCLC for the first time. We proved that AdipoRon strongly inhibits viability, growth and colony formation in H1299 and A549 NSCLC cells, mainly through a slowdown in cell cycle progression. Along with the biological behaviors, a metabolic switching was observed after AdipoRon administration in NSCLC cells, consisting of higher glucose consumption and lactate accumulation. Remarkably, both 2-Deoxy Glucose and Oxamate glycolytic-interfering agents greatly enhanced AdipoRon’s antiproliferative features. As a master regulator of cell metabolism, AMP-activated protein kinase (AMPK) was activated by AdipoRon. Notably, the ablation of AdipoRon-induced AMPK phosphorylation by Compound-C significantly counteracted its effectiveness. However, the engagement of other pathways should be investigated afterwards. With a focus on NSCLC, our findings further support the ability of AdipoRon in acting as an anticancer molecule, driving its endorsement as a future candidate in NSCLC therapy. Full article

Cytochrome c (Cytc) is important for both mitochondrial respiration and apoptosis, both of which are altered in cancer cells that switch to Warburg metabolism and manage to evade apoptosis. We earlier reported that lysine 53 (K53) of Cytc is acetylated in prostate cancer. K53 is conserved in mammals that is known to be essential for binding to cytochrome c oxidase and apoptosis protease activating factor-1 (Apaf-1). Here we report the effects of this acetylation on the main functions of cytochrome c by expressing acetylmimetic K53Q in cytochrome c double knockout cells. Other cytochrome c variants analyzed were wild-type, K53R as a control that maintains the positive charge, and K53I, which is present in some non-mammalian species. Intact cells expressing K53Q cytochrome c showed 49% decreased mitochondrial respiration and a concomitant increase in glycolytic activity (Warburg effect). Furthermore, mitochondrial membrane potential was decreased, correlating with notably reduced basal mitochondrial superoxide levels and decreased cell death upon challenge with H₂O₂ or staurosporine. To test for markers of cancer aggressiveness and invasiveness, cells were grown in 3D spheroid culture. K53Q cytochrome c-expressing cells showed profoundly increased protrusions compared to WT, suggesting increased invasiveness. We propose that K53 acetylation of cytochrome c is an adaptive response that mediates prostate cancer metabolic reprogramming and evasion of apoptosis, which are two hallmarks of cancer, to better promote tumor survival and metastasis. Full article

Glioblastoma (GBM) is one of the most aggressive and devastating primary brain tumors, with a median survival of 15 months following diagnosis. Despite the intense treatment regimen which routinely includes maximal safe neurosurgical resection followed by adjuvant radio- and chemotherapy, the disease remains uniformly fatal. The poor prognosis associated with GBM is multifactorial owing to factors such as increased proliferation, angiogenesis, and metabolic switching to glycolytic pathways. Critically, GBM-mediated local and systemic immunosuppression result in inadequate immune surveillance and ultimately, tumor-immune escape. Microglia—the resident macrophages of the central nervous system (CNS)—play crucial roles in mediating the local immune response in the brain. Depending on the specific pathological cues, microglia are activated into either a pro-inflammatory, neurotoxic phenotype, known as M1, or an anti-inflammatory, regenerative phenotype, known as M2. In either case, microglia secrete corresponding pro- or anti-inflammatory cytokines and chemokines that either promote or hinder tumor growth. Herein, we review the interplay between GBM cells and resident microglia with a focus on contemporary studies highlighting the effect of GBM on the subtypes of microglia expressed, the associated cytokines/chemokines secreted, and ultimately, their impact on tumor pathogenesis. Finally, we explore how understanding the intricacies of the tumor-immune landscape can inform novel immunotherapeutic strategies against this devastating disease. Full article

Energy metabolism plays a pivotal role in the pathogenesis of endometriosis. For the initial stages of the disease in adolescents, this aspect remains unexplored. The objective of this paper was to analyze the association of cellular and endosomal profiles of markers of glycolysis, mitochondrial biogenesis, apoptosis, autophagy and estrogen signaling in peritoneal endometriosis (PE) in adolescents. We included 60 girls aged 13–17 years in a case–control study: 45 with laparoscopically confirmed PE (main group) and 15 with paramesonephric cysts (comparison group). Samples of plasma and peritoneal fluid exosomes, endometrioid foci and non-affected peritoneum were tested for estrogen receptor (Erα/β), hexokinase (Hex2), pyruvate dehydrogenase kinase (PDK1), glucose transporter (Glut1), monocarboxylate transporters (MCT1 and MCT2), optic atrophy 1 (OPA1, mitochondrial fusion protein), dynamin-related protein 1 (DRP1, mitochondrial fission protein), Bax, Bcl2, Beclin1, Bnip3, P38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor 1 (Hif-1α), mitochondrial voltage-dependent anion channel (VDAC) and transforming growth factor (TGFβ) proteins as markers of estrogen signaling, glycolysis rates, mitochondrial biogenesis and damage, apoptosis and autophagy (Western-Blot and PCR). The analysis identified higher levels of molecules associated with proliferation (ERβ), glycolysis (MCT2, PDK1, Glut1, Hex2, TGFβ and Hif-1α), mitochondrial biogenesis (OPA1, DRP1) and autophagy (P38, Beclin1 and Bnip3) and decreased levels of apoptosis markers (Bcl2/Bax) in endometrioid foci compared to non-affected peritoneum and that in the comparison group (p < 0.05). Patients with PE had altered profiles of ERβ in plasma and peritoneal fluid exosomes and higher levels of Glut1, MCT2 and Bnip3 in plasma exosomes (p < 0.05). The results of the differential expression profiles indicate microenvironment modification, mitochondrial biogenesis, estrogen reception activation and glycolytic switch along with apoptosis suppression in peritoneal endometrioid foci already in adolescents. Full article

This work was aimed at the complex analysis of the metabolic and oxygen statuses of tumors in vivo after photodynamic therapy (PDT). Studies were conducted on mouse tumor model using two types of photosensitizers—chlorin e6-based drug Photoditazine predominantly targeted to the vasculature and genetically encoded photosensitizer KillerRed targeted to the chromatin. Metabolism of tumor cells was assessed by the fluorescence lifetime of the metabolic redox-cofactor NAD(P)H, using fluorescence lifetime imaging. Oxygen content was assessed using phosphorescence lifetime macro-imaging with an oxygen-sensitive probe. For visualization of the perfused microvasculature, an optical coherence tomography-based angiography was used. It was found that PDT induces different alterations in cellular metabolism, depending on the degree of oxygen depletion. Moderate decrease in oxygen in the case of KillerRed was accompanied by an increase in the fraction of free NAD(P)H, an indicator of glycolytic switch, early after the treatment. Severe hypoxia after PDT with Photoditazine resulted from a vascular shutdown yielded in a persistent increase in protein-bound (mitochondrial) fraction of NAD(P)H. These findings improve our understanding of physiological mechanisms of PDT in cellular and vascular modes and can be useful to develop new approaches to monitoring its efficacy. Full article

The application of doxorubicin (DOX) is hampered by cardiotoxicity, with diastolic dysfunction as the earliest manifestation. Fibrosis leads to impaired relaxation, but the mechanisms that operate shortly after DOX exposure are not clear. We asked whether the activation of cardiac fibroblasts (CFs) anticipates myocardial dysfunction and evaluated the effects of DOX on CF metabolism. CFs were isolated from the hearts of rats after the first injection of DOX. In another experiment, CFs were exposed to DOX in vitro. Cell phenotype and metabolism were determined. Early effects of DOX consisted of diastolic dysfunction and unchanged ejection fraction. Markers of pro-fibrotic remodeling and evidence of CF transformation were present immediately after treatment completion. Oxygen consumption rate and extracellular acidification revealed an increased metabolic activity of CFs and a switch to glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naïve CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs that upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling. In conclusion, the metabolic switch and activation of CFs anticipate DOX-induced damage and represent a novel target in the early phase of anthracycline cardiomyopathy. Full article

The present study aimed to investigate the effect of APIC, a mixture containing soy isoflavone and L-carnitine on running endurance. Male C57BL/6 mice were orally administered APIC for 8 weeks. The APIC group exhibited a significant increase in treadmill running time until exhaustion compared to the control group. The respiratory exchange ratio in the APIC group was lower, indicating an enhancement in fatty acid oxidative metabolism. Furthermore, APIC supplementation increased the proportion of oxidative myofibers. Biochemical parameters associated with endurance capacity were also affected by APIC, as evidenced by increased muscle ATP levels and decreased levels of muscle triglycerides and blood lactate. qPCR and immunoblot analysis of C2C12 myotubes and gastrocnemius muscles indicated that APIC treatment stimulated AMPK signaling, mitochondrial biogenesis, and fatty acid metabolism. Additionally, treatment with APIC led to an increased oxygen consumption rate in C2C12 myotubes. Collectively, these findings suggest that APIC supplementation enhances mitochondrial biogenesis, promotes a switch from glycolytic to oxidative fiber types, and improves fatty acid metabolism through the activation of the AMPK signaling pathway in murine skeletal muscle. Ultimately, these effects contribute to the enhancement of running endurance. Full article

The interplay between hypoxia-inducible factors (HIFs) and transforming growth factor beta (TGF-β) is critical for both inflammation and angiogenesis. In hereditary hemorrhagic telangiectasia (HHT), we have previously observed that impairment of the TGF-β pathway is associated with downregulation of HIF-1α. HIF-1α accumulation is mandatory in situations of altered energy demand, such as during infection or hypoxia, by adjusting cell metabolism. Leukocytes undergo a HIF-1α-dependent switch from aerobic mitochondrial respiration to anaerobic glycolysis (glycolytic switch) after stimulation and during differentiation. We postulate that the decreased HIF-1α accumulation in HHT leads to a clinically observed immunodeficiency in these patients. Examination of HIF-1α and its target genes in freshly isolated peripheral blood mononuclear cells (PBMCs) from HHT patients revealed decreased gene expression and protein levels of HIF-1α and HIF-1α-regulated glycolytic enzymes. Treatment of these cells with the HIF–prolyl hydroxylase inhibitor, Roxadustat, rescued their ability to accumulate HIF-1α protein. Functional analysis of metabolic flux using a Seahorse FX extracellular flux analyzer showed that the extracellular acidification rate (indicator of glycolytic turnover) after Roxadustat treatment was comparable to non-HHT controls, while oxygen consumption (indicator of mitochondrial respiration) was slightly reduced. HIF stabilization may be a potential therapeutic target in HHT patients suffering from infections. Full article

The study of the mechanisms underlying stem cell differentiation is under intensive research and includes the contribution of a metabolic switch from glycolytic to oxidative metabolism. While mitochondrial biogenesis has been previously demonstrated in number of differentiation models, it is only recently that the role of mitochondrial dynamics has started to be explored. The discovery of asymmetric distribution of mitochondria in stem cell progeny has strengthened the interest in the field. This review attempts to summarize the regulation of mitochondrial asymmetric apportioning by the mitochondrial fusion, fission, and mitophagy processes as well as emphasize how asymmetric mitochondrial apportioning in stem cells affects their metabolism, and thus epigenetics, and determines cell fate. Full article

Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesis, the fiber-type switch from oxidative to glycolytic fibers, and enhanced angiogenesis. To assess the role of THs on the lipidic composition of SkM fibers, we performed lipidomic analyses of SkM cells and tissues, glucose tolerance experiments, and exercise performance tests. Our data demonstrated that TH treatment induces remodeling of the lipid profile and changes the proportion of fatty acids in SkM. In brief, THs significantly reduced the ratio of stearic/oleic acid in the muscle similar to what is induced by physical activity. The increased proportion of unsaturated fatty acids was linked to an improvement in insulin sensitivity and endurance exercise. These findings point to THs as critical endocrine factors affecting exercise performance and indicate that homeostatic maintenance of TH signals, by improving cell permeability and receptor stability at the cell membrane, is crucial for muscle physiology. Full article

Hepatocellular cancer (HCC) is the most common primary liver cancer and the third leading cause of cancer-related death. Locoregional therapies, including transarterial embolization (TAE: bland embolization), chemoembolization (TACE), and radioembolization, have demonstrated survival benefits when treating patients with unresectable HCC. TAE and TACE occlude the tumor’s arterial supply, causing hypoxia and nutritional deprivation and ultimately resulting in tumor necrosis. Embolization blocks the aerobic metabolic pathway. However, tumors, including HCC, use the “Warburg effect” and survive hypoxia from embolization. An adaptation to hypoxia through the Warburg effect, which was first described in 1956, is when the cancer cells switch to glycolysis even in the presence of oxygen. Hence, this is also known as aerobic glycolysis. In this article, the adaptation mechanisms of HCC, including glycolysis, are discussed, and anti-glycolytic treatments, including systemic and locoregional options that have been previously reported or have the potential to be utilized in the treatment of HCC, are reviewed. Full article

A mathematical model of energy metabolism in erythrocyte-bioreactors loaded with alcohol dehydrogenase and acetaldehyde dehydrogenase was constructed and analyzed. Such erythrocytes can convert ethanol to acetate using intracellular NAD and can therefore be used to treat alcohol intoxication. Analysis of the model revealed that the rate of ethanol consumption by the erythrocyte-bioreactors increases proportionally to the activity of incorporated ethanol-consuming enzymes until their activity reaches a specific threshold level. When the ethanol-consuming enzyme activity exceeds this threshold, the steady state in the model becomes unstable and the model switches to an oscillation mode caused by the competition between glyceraldehyde phosphate dehydrogenase and ethanol-consuming enzymes for NAD. The amplitude and period of metabolite oscillations first increase with the increase in the activity of the encapsulated enzymes. A further increase in these activities leads to a loss of the glycolysis steady state, and a permanent accumulation of glycolytic intermediates. The oscillation mode and the loss of the steady state can lead to the osmotic destruction of erythrocyte-bioreactors due to an accumulation of intracellular metabolites. Our results demonstrate that the interaction of enzymes encapsulated in erythrocyte-bioreactors with erythrocyte metabolism should be taken into account in order to achieve the optimal efficacy of these bioreactors. Full article

Mitochondria are important organelles for cellular physiology as they generate most of the energy requirements of the cell and orchestrate many biological functions. Dysregulation of mitochondrial function is associated with many pathological conditions, including cancer development. Mitochondrial glucocorticoid receptor (mtGR) is proposed as a crucial regulator of mitochondrial functions via its direct involvement in the regulation of mitochondrial transcription, oxidative phosphorylation (OXPHOS), enzymes biosynthesis, energy production, mitochondrial-dependent apoptosis, and regulation of oxidative stress. Moreover, recent observations revealed the interaction of mtGR with the pyruvate dehydrogenase (PDH), a key player in the metabolic switch observed in cancer, indicating direct involvement of mtGR in cancer development. In this study, by using a xenograft mouse model of mtGR-overexpressing hepatocarcinoma cells, we showed increased mtGR-associated tumor growth, which is accompanied by reduced OXPHOS biosynthesis, reduction in PDH activity, and alterations in the Krebs cycle and glucose metabolism, metabolic alterations similar to those observed in the Warburg effect. Moreover, autophagy activation is observed in mtGR-associated tumors, which further support tumor progression via increased precursors availability. Thus, we propose that increased mitochondrial localization of mtGR is associated with tumor progression possible via mtGR/PDH interaction, which could lead to suppression of PDH activity and modulation of mtGR-induced mitochondrial transcription that ends up in reduced OXPHOS biosynthesis and reduced oxidative phosphorylation versus glycolytic pathway energy production, in favor of cancer cells. Full article

Cancer cells undergo metabolic reprogramming and switch to a ‘glycolysis-dominant’ metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the ‘Warburg effect,’ provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy. Full article