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Function (Oxford, England) 2023
Topics: Oxidative Phosphorylation; Adenosine Triphosphate
PubMed: 37799324
DOI: 10.1093/function/zqad051 -
Oncology Reports Mar 2022Therapeutic approaches that target the metabolism of tumor cells have been a popular research topic in recent years. Previous studies have demonstrated that glycolysis... (Review)
Review
Therapeutic approaches that target the metabolism of tumor cells have been a popular research topic in recent years. Previous studies have demonstrated that glycolysis inhibitors reduce the proliferation of non‑small cell lung cancer (NSCLC) cells by interfering with the aerobic glycolytic pathway. However, the mitochondrial oxidative phosphorylation (OXPHOS) pathway in tumor cells has also been implicated in lung cancer metabolism. Metformin, a known inhibitor of mitochondrial OXPHOS, has been indicated to reduce NSCLC morbidity and mortality in clinical studies. The present article reviewed the therapeutic effects of metformin against NSCLC, both as a single agent and combined with other anticancer treatments, in order to provide a theoretical basis for its clinical use in adjuvant therapy for NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Drug Therapy, Combination; Glycolysis; Humans; Hypoglycemic Agents; Lung Neoplasms; Metformin; Mitochondria; Oxidative Phosphorylation
PubMed: 35039878
DOI: 10.3892/or.2022.8266 -
Scientific Reports Oct 2019Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative...
Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats.
Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein + 3% leucine]). After 20 days of tumour evolution, the animals underwent -fludeoxyglucose positron emission computed tomography (F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
Topics: Animals; Carcinoma 256, Walker; Female; Food, Formulated; Glucose; Glycolysis; Leucine; Neoplasm Metastasis; Oxidative Phosphorylation; Rats; Rats, Wistar
PubMed: 31664147
DOI: 10.1038/s41598-019-52112-w -
Journal of Translational Medicine May 2021Generally, cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. However, the...
BACKGROUND
Generally, cancer cells undergo metabolic reprogramming to adapt to energetic and biosynthetic requirements that support their uncontrolled proliferation. However, the mutual relationship between two critical metabolic pathways, glycolysis and oxidative phosphorylation (OXPHOS), remains poorly defined.
METHODS
We developed a "double-score" system to quantify glycolysis and OXPHOS in 9668 patients across 33 tumor types from The Cancer Genome Atlas and classified them into four metabolic subtypes. Multi-omics bioinformatical analyses was conducted to detect metabolism-related molecular features.
RESULTS
Compared with patients with low glycolysis and high OXPHOS (LGHO), those with high glycolysis and low OXPHOS (HGLO) were consistently associated with worse prognosis. We identified common dysregulated molecular features between different metabolic subgroups across multiple cancers, including gene, miRNA, transcription factor, methylation, and somatic alteration, as well as investigated their mutual interfering relationships.
CONCLUSION
Overall, this work provides a comprehensive atlas of metabolic heterogeneity on a pan-cancer scale and identified several potential drivers of metabolic rewiring, suggesting corresponding prognostic and therapeutic utility.
Topics: Biomarkers; Glycolysis; Humans; MicroRNAs; Neoplasms; Oxidative Phosphorylation
PubMed: 34030708
DOI: 10.1186/s12967-021-02889-0 -
Bulletin of Mathematical Biology Oct 2021Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates...
Metabolic behaviours of proliferating cells are often explained as a consequence of rational optimization of cellular growth rate, whereas microeconomics formulates consumption behaviours as optimization problems. Here, we pushed beyond the analogy to precisely map metabolism onto the theory of consumer choice. We thereby revealed the correspondence between long-standing mysteries in both fields: the Warburg effect, a seemingly wasteful but ubiquitous strategy where cells favour aerobic glycolysis over more energetically efficient oxidative phosphorylation, and Giffen behaviour, the unexpected consumer behaviour where a good is demanded more as its price rises. We identified the minimal, universal requirements for the Warburg effect: a trade-off between oxidative phosphorylation and aerobic glycolysis and complementarity, i.e. impossibility of substitution for different metabolites. Thus, various hypotheses for the Warburg effect are integrated into an identical optimization problem with the same universal structure. Besides, the correspondence between the Warburg effect and Giffen behaviour implies that oxidative phosphorylation is counter-intuitively stimulated when its efficiency is decreased by metabolic perturbations such as drug administration or mitochondrial dysfunction; the concept of Giffen behaviour bridges the Warburg effect and the reverse Warburg effect. This highlights that the application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.
Topics: Glycolysis; Humans; Mathematical Concepts; Models, Biological; Neoplasms; Oxidative Phosphorylation
PubMed: 34718881
DOI: 10.1007/s11538-021-00952-x -
QJM : Monthly Journal of the... Jun 2016Glucose and glutamine metabolism in cancer cells are markedly elevated relative to non-transformed normal cells. This metabolic reprogramming enables the production of... (Review)
Review
Glucose and glutamine metabolism in cancer cells are markedly elevated relative to non-transformed normal cells. This metabolic reprogramming enables the production of adenosine triphosphate and the anabolic precursors needed for survival, growth and motility. The recent observations that mutant oncogenic proteins and the loss of tumor suppressors activate key metabolic enzymes suggest that selective inhibition of these enzymes may yield effective cancer therapeutics with acceptable toxicities. In support of this concept, pre-clinical studies of small molecule antagonists of several metabolic enzymes in tumor-bearing mice have demonstrated reasonable therapeutic indices. We will review the rationale for targeting metabolic enzymes as a strategy to treat cancer and will detail the results of several recent clinical trials of metabolic inhibitors in advanced cancer patients.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Drug Design; Energy Metabolism; Gene Expression Regulation, Neoplastic; Humans; Molecular Targeted Therapy; Neoplasms; Oxidative Phosphorylation; Tumor Microenvironment
PubMed: 26428335
DOI: 10.1093/qjmed/hcv181 -
The Journal of Physiology Dec 19861. In the taenia from the guinea-pig caecum, the relative contribution of glycolysis and oxidative phosphorylation to activation of the Na pump was estimated by...
1. In the taenia from the guinea-pig caecum, the relative contribution of glycolysis and oxidative phosphorylation to activation of the Na pump was estimated by measuring changes in the rate of O2 consumption (QO2) and lactate production (Q1act). The Na pump was activated by K readmission following prior treatment with K-free solution. The QO2 and Q1act were both increased significantly by K readmission 60 min after exposure to K-free solution. These changes and the reaccumulation of tissue K were abolished by ouabain (10 microM). Spontaneous mechanical activity ceased in K-free solution and the K-induced increase in QO2 and Q1act was produced before the mechanical activity was restarted. 2. Similar changes were obtained when ouabain (10 microM) was removed after 60 min treatment. It was estimated from the changes in QO2 and Q1act that the oxidative and glycolytic metabolism each supplied about 50% of the total ATP demand for pump activation. 3. In Ca-free solution, the increase in QO2 caused by K readmission was transient and QO2 returned to the previous value in K-free solution in 10-20 min. However, the increase in QO2 was maintained in the absence of glucose. When glucose was replaced with beta-hydroxybutyrate (beta-HB, 11.8 mM), which is metabolized only through oxidative phosphorylation, K readmission also produced a sustained increase in QO2. 4. In glycogen-depleted preparations, K readmission produced little or no increase in QO2 in the absence of substrate or in the presence of glucose. On the other hand, in the presence of beta-HB (11.8 mM), a typical increase in QO2 (about 0.1 mumol min-1 g-1) was observed in response to K readmission. Lactate production was negligible in the absence of substrate or in the presence of beta-HB, but it was significantly increased after K readmission in the presence of glucose. The increase in tissue K content following K readmission was the same in the presence of glucose or beta-HB. 5. In the glycogen-depleted preparations the increase in QO2 caused by beta-HB was dependent on the presence of both Na and K in the medium, and sensitive to ouabain. Furthermore, this response was reversibly suppressed by glucose.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Cecum; Female; Glucose; Glycolysis; Guinea Pigs; In Vitro Techniques; Ion Channels; Isometric Contraction; Male; Muscle, Smooth; Ouabain; Oxidative Phosphorylation; Oxygen Consumption; Potassium; Sodium
PubMed: 2442356
DOI: 10.1113/jphysiol.1986.sp016313 -
Journal of Bioenergetics and... Jun 2021In vivo associations of respiratory complexes forming higher supramolecular structures are generally accepted nowadays. Supercomplexes (SC) built by complexes I, III and...
In vivo associations of respiratory complexes forming higher supramolecular structures are generally accepted nowadays. Supercomplexes (SC) built by complexes I, III and IV and the so-called respirasome (I/III/IV) have been described in mitochondria from several model organisms (yeasts, mammals and green plants), but information is scarce in other lineages. Here we studied the supramolecular associations between the complexes I, III, IV and V from the secondary photosynthetic flagellate Euglena gracilis with an approach that involves the extraction with several mild detergents followed by native electrophoresis. Despite the presence of atypical subunit composition and additional structural domains described in Euglena complexes I, IV and V, canonical associations into III/IV, III/IV SCs and I/III/IV respirasome were observed together with two oligomeric forms of the ATP synthase (V and V). Among them, III/IV SC could be observed by electron microscopy. The respirasome was further purified by two-step liquid chromatography and showed in-vitro oxygen consumption independent of the addition of external cytochrome c.
Topics: Animals; Euglena gracilis; Oxidative Phosphorylation
PubMed: 33646522
DOI: 10.1007/s10863-021-09882-8 -
Environment International Apr 2024Exposure to bisphenol S (BPS) is known to adversely affect neuronal development. As pivotal components of neuronal polarization, axons and dendrites are indispensable...
Exposure to bisphenol S (BPS) is known to adversely affect neuronal development. As pivotal components of neuronal polarization, axons and dendrites are indispensable structures within neurons, crucial for the maintenance of nervous system function. Here, we investigated the impact of BPS exposure on axonal and dendritic development both in vivo and in vitro. Our results revealed that exposure to BPS during pregnancy and lactation led to a reduction in the complexity, density, and length of axons and dendrites in the prefrontal cortex (PFC) of offspring. Employing RNA sequencing technology to elucidate the underlying mechanisms of axonal and dendritic damage induced by BPS, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted a significant alteration in the oxidative phosphorylation (OXPHOS) pathway, essential for mitochondrial function. Subsequent experiments demonstrate BPS-induced impairment in mitochondrial function, including damaged morphology, decreased adenosine triphosphate (ATP) and superoxide dismutase (SOD) levels, and increased reactive oxygen species and malondialdehyde (MDA). These alterations coincided with the downregulated expression of OXPHOS pathway-related genes (ATP6V1B1, ATP5K, NDUFC1, NDUFC2, NDUFA3, COX6B1) and Myosin 19 (Myo19). Notably, Myo19 overexpression restored the BPS-induced mitochondrial dysfunction by alleviating the inhibition of OXPHOS pathway. Consequently, this amelioration was associated with a reduction in BPS-induced axonal and dendritic injury observed in cultured neurons of the PFC.
Topics: Animals; Mitochondria; Phenols; Dendrites; Oxidative Phosphorylation; Female; Sulfones; Axons; Pregnancy; Prefrontal Cortex; Mice
PubMed: 38615544
DOI: 10.1016/j.envint.2024.108643 -
Nutrients Sep 2017In human cells, mitochondria provide the largest part of cellular energy in the form of adenosine triphosphate generated by the process of oxidative phosphorylation... (Review)
Review
In human cells, mitochondria provide the largest part of cellular energy in the form of adenosine triphosphate generated by the process of oxidative phosphorylation (OXPHOS). Impaired OXPHOS activity leads to a heterogeneous group of inherited diseases for which therapeutic options today remain very limited. Potential innovative strategies aim to ameliorate mitochondrial function by increasing the total mitochondrial load of tissues and/or to scavenge the excess of reactive oxygen species generated by OXPHOS malfunctioning. In this respect, resveratrol, a compound that conveniently combines mitogenetic with antioxidant activities and, as a bonus, possesses anti-apoptotic properties, has come forward as a promising nutraceutical. We review the scientific evidence gathered so far through experiments in both in vitro and in vivo systems, evaluating the therapeutic effect that resveratrol is expected to generate in mitochondrial patients. The obtained results are encouraging, but clearly show that achieving normalization of OXPHOS function with this strategy alone could prove to be an unattainable goal.
Topics: Adenosine Triphosphate; Apoptosis; Dietary Supplements; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation; Reactive Oxygen Species; Resveratrol; Stilbenes
PubMed: 28906460
DOI: 10.3390/nu9091017