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Molecules (Basel, Switzerland) Dec 2016This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the "Warburg" and "Crabtree" effects. This work... (Review)
Review
This review summarizes the current state of knowledge about the metabolism of cancer cells, especially with respect to the "Warburg" and "Crabtree" effects. This work also summarizes two key discoveries, one of which relates to hexokinase-2 (HK2), a major player in both the "Warburg effect" and cancer cell immortalization. The second discovery relates to the finding that cancer cells, unlike normal cells, derive as much as 60% of their ATP from glycolysis via the "Warburg effect", and the remaining 40% is derived from mitochondrial oxidative phosphorylation. Also described are selected anticancer agents which generally act as strong energy blockers inside cancer cells. Among them, much attention has focused on 3-bromopyruvate (3BP). This small alkylating compound targets both the "Warburg effect", i.e., elevated glycolysis even in the presence oxygen, as well as mitochondrial oxidative phosphorylation in cancer cells. Normal cells remain unharmed. 3BP rapidly kills cancer cells growing in tissue culture, eradicates tumors in animals, and prevents metastasis. In addition, properly formulated 3BP shows promise also as an effective anti-liver cancer agent in humans and is effective also toward cancers known as "multiple myeloma". Finally, 3BP has been shown to significantly extend the life of a human patient for which no other options were available. Thus, it can be stated that 3BP is a very promising new anti-cancer agent in the process of undergoing clinical development.
Topics: Antineoplastic Agents; Energy Metabolism; Glycolysis; Hexokinase; Humans; Liver Neoplasms; Mitochondria; Multiple Myeloma; Oxidative Phosphorylation; Pyruvates
PubMed: 27983708
DOI: 10.3390/molecules21121730 -
Journal of Inherited Metabolic Disease Jul 2015Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date... (Review)
Review
Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders.
Topics: Energy Metabolism; Humans; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 25778941
DOI: 10.1007/s10545-015-9831-y -
Annals of Botany Apr 2020Mitochondria play a diversity of physiological and metabolic roles under conditions of abiotic or biotic stress. They may be directly subjected to physico-chemical... (Review)
Review
BACKGROUND
Mitochondria play a diversity of physiological and metabolic roles under conditions of abiotic or biotic stress. They may be directly subjected to physico-chemical constraints, and they are also involved in integrative responses to environmental stresses through their central position in cell nutrition, respiration, energy balance and biosyntheses. In plant cells, mitochondria present various biochemical peculiarities, such as cyanide-insensitive alternative respiration, and, besides integration with ubiquitous eukaryotic compartments, their functioning must be coupled with plastid functioning. Moreover, given the sessile lifestyle of plants, their relative lack of protective barriers and present threats of climate change, the plant cell is an attractive model to understand the mechanisms of stress/organelle/cell integration in the context of environmental stress responses.
SCOPE
The involvement of mitochondria in this integration entails a complex network of signalling, which has not been fully elucidated, because of the great diversity of mitochondrial constituents (metabolites, reactive molecular species and structural and regulatory biomolecules) that are linked to stress signalling pathways. The present review analyses the complexity of stress signalling connexions that are related to the mitochondrial electron transport chain and oxidative phosphorylation system, and how they can be involved in stress perception and transduction, signal amplification or cell stress response modulation.
CONCLUSIONS
Plant mitochondria are endowed with a diversity of multi-directional hubs of stress signalling that lead to regulatory loops and regulatory rheostats, whose functioning can amplify and diversify some signals or, conversely, dampen and reduce other signals. Involvement in a wide range of abiotic and biotic responses also implies that mitochondrial stress signalling could result in synergistic or conflicting outcomes during acclimation to multiple and complex stresses, such as those arising from climate change.
Topics: Electron Transport; Oxidative Phosphorylation; Oxidative Stress; Plants; Reactive Oxygen Species; Signal Transduction; Stress, Physiological
PubMed: 31711195
DOI: 10.1093/aob/mcz184 -
The FEBS Journal Mar 2007In early studies on energy metabolism of tumor cells, it was proposed that the enhanced glycolysis was induced by a decreased oxidative phosphorylation. Since then it... (Review)
Review
In early studies on energy metabolism of tumor cells, it was proposed that the enhanced glycolysis was induced by a decreased oxidative phosphorylation. Since then it has been indiscriminately applied to all types of tumor cells that the ATP supply is mainly or only provided by glycolysis, without an appropriate experimental evaluation. In this review, the different genetic and biochemical mechanisms by which tumor cells achieve an enhanced glycolytic flux are analyzed. Furthermore, the proposed mechanisms that arguably lead to a decreased oxidative phosphorylation in tumor cells are discussed. As the O(2) concentration in hypoxic regions of tumors seems not to be limiting for the functioning of oxidative phosphorylation, this pathway is re-evaluated regarding oxidizable substrate utilization and its contribution to ATP supply versus glycolysis. In the tumor cell lines where the oxidative metabolism prevails over the glycolytic metabolism for ATP supply, the flux control distribution of both pathways is described. The effect of glycolytic and mitochondrial drugs on tumor energy metabolism and cellular proliferation is described and discussed. Similarly, the energy metabolic changes associated with inherent and acquired resistance to radiotherapy and chemotherapy of tumor cells, and those determined by positron emission tomography, are revised. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors.
Topics: Energy Metabolism; Glycolysis; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Protein Isoforms
PubMed: 17302740
DOI: 10.1111/j.1742-4658.2007.05686.x -
Journal of Industrial Microbiology &... Dec 2021Two new tetramic acid derivatives, traminines A (1) and B (2), were isolated from a culture broth of Fusarium concentricum FKI-7550 by bioassay-guided fractionation...
Two new tetramic acid derivatives, traminines A (1) and B (2), were isolated from a culture broth of Fusarium concentricum FKI-7550 by bioassay-guided fractionation using multidrug-sensitive Saccharomyces cerevisiae 12geneΔ0HSR-iERG6. The chemical structures of 1 and 2 were elucidated by NMR studies. Compounds 1 and 2 inhibited the growth of the multidrug-sensitive yeast strain on nonfermentable medium containing glycerol, but not on fermentable medium containing glucose. These results strongly suggest that they target mitochondrial machineries presiding over ATP production via oxidative phosphorylation. Throughout the assay monitoring overall ADP-uptake/ATP-release in yeast mitochondria, 1 and 2 were shown to inhibit one or more enzymes involving oxidative phosphorylation. Based on biochemical characterization, we found that the interference with oxidative phosphorylation by 1 is attributable to the dual inhibition of complex III and FoF1-ATPase, whereas that by 2 is solely due to the inhibition of complex III.
Topics: Fusarium; Mitochondria; Oxidative Phosphorylation; Saccharomyces cerevisiae
PubMed: 34343309
DOI: 10.1093/jimb/kuab051 -
Frontiers in Cellular and Infection... 2022Colibacillosis is one of the major health threats in the poultry industry worldwide. Understanding the pathogenic mechanisms involved in -induced inflammatory response...
Colibacillosis is one of the major health threats in the poultry industry worldwide. Understanding the pathogenic mechanisms involved in -induced inflammatory response may lead to the development of new therapies to combat the disease. To address this, a total of 96 1-day-old male lean Pekin ducklings were employed and randomly allocated to two treatments, each with six replicates of eight ducks. Ducks in the experiment group (EG) and the control group (CG) were separately orally administered with 0.2 ml of pathogenic O88 (3 × 10 CFU/ml) or equivalent volumes of 0.9% sterile saline solution on day 7, two times with an 8-h interval. Serum and intestinal samples were collected on days 9, 14, and 28. Results showed that ducks challenged with had lower average daily gain and higher feed intake/weight gain during days 9-14 and overall (< 0.05). Histopathological examination showed that decreased the villus height and the ratio of villus height/crypt depth in the jejunum (< 0.05) on days 9 and 14. The intestinal barrier was disrupted, presenting in ducks having higher serum DAO and D-LA on days 9 and 14 (< 0.05) and greater content of serum LPS on day 9 (< 0.05). infection also triggered a systemic inflammatory response including the decrease of the serum IgA, IgM, and jejunal sIgA on day 14 (< 0.05). In addition to these, 1,062 differentially expressed genes were detected in the jejunum tissues of ducks by RNA-seq, consisting of 491 upregulated and 571 downregulated genes. Based on the KEGG database, oxidative phosphorylation and the ribosome pathway were the most enriched. These findings reveal the candidate pathways and genes that may be involved in infection, allow a better understanding of the molecular mechanisms of inflammation progression and may facilitate the genetic improvement of ducks, and provide further insights to tackle the drug sensitivity and animal welfare issues.
Topics: Animal Feed; Animals; Diet; Dietary Supplements; Ducks; Escherichia coli; Male; Oxidative Phosphorylation; Ribosomes
PubMed: 36061867
DOI: 10.3389/fcimb.2022.940847 -
Animal : An International Journal of... Jan 2021Compensatory growth (CG) is a naturally accelerated growth which occurs upon realimentation, following a prior period of dietary restriction. The process is harnessed...
Compensatory growth (CG) is a naturally accelerated growth which occurs upon realimentation, following a prior period of dietary restriction. The process is harnessed worldwide as a management practice to reduce feed costs in beef cattle production. The objective of this study was to assess the potential contribution of hepatic cellular mitochondrial capacity to CG through global hepatic oxidative phosphorylation gene expression analyses as well as functional mitochondrial enzyme activity assays. Holstein-Friesian bulls were separated into two groups: (i) restricted feed allowance for 125 days (Period 1) (RES; n = 30) followed by ad-libitum feeding for 55 days (Period 2) or (ii) ad-libitum access to feed throughout (Periods 1 and 2) (ADLIB; n = 30). At the end of each period, 15 animals from each treatment group were slaughtered and hepatic tissue was collected. Tissue samples were subjected to RNAseq and spectrophotometric analysis for the functional assessment of mitochondria. RES and ADLIB groups grew at 0.6 kg/day and 1.9 kg/day, respectively, during Period 1. During Period 2, the RES group underwent CG growing at 2.5 kg/day, with ADLIB animals gaining 1.4 kg/day. Oxidative phosphorylation genes were differentially expressed in response to both dietary restriction and CG. Spectrophotometric assays indicated that mitochondrial abundance was greater in animals undergoing dietary restriction at the end of Period 1 and subsequently reduced during realimentation (P < 0.02). Results indicate that mitochondrial capacity may be enhanced during dietary restriction to more effectively utilize diet-derived nutrients. However, enhanced mitochondrial capacity does not appear to be directly contributing to CG in cattle.
Topics: Animal Feed; Animals; Cattle; Diet; Food Deprivation; Liver; Male; Oxidative Phosphorylation
PubMed: 33516006
DOI: 10.1016/j.animal.2020.100009 -
Immunity Sep 2017In this issue of Immunity, Riffelmacher et al. (2017) show that autophagy is necessary for the release of free fatty acids from intracellular stores within neutrophil...
In this issue of Immunity, Riffelmacher et al. (2017) show that autophagy is necessary for the release of free fatty acids from intracellular stores within neutrophil precursor cells. This limits glycolysis, increases oxidative phosphorylation, and is essential for neutrophil maturation.
Topics: Autophagy; Humans; Neutrophils; Oxidative Phosphorylation
PubMed: 28930652
DOI: 10.1016/j.immuni.2017.08.013 -
Tumour Biology : the Journal of the... Oct 2020Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways... (Review)
Review
Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.
Topics: Antineoplastic Agents; Citric Acid Cycle; Energy Metabolism; Gene Expression Regulation, Neoplastic; Glucose; Glycolysis; Humans; Molecular Targeted Therapy; Neoplasms; Oxidative Phosphorylation; Pentose Phosphate Pathway; Precision Medicine
PubMed: 33028168
DOI: 10.1177/1010428320965284 -
Aging Mar 2024Osteosarcoma is a prevalent malignant tumor that originates from mesenchymal tissue. It typically affects children and adolescents. Although it is known that the growth...
BACKGROUND
Osteosarcoma is a prevalent malignant tumor that originates from mesenchymal tissue. It typically affects children and adolescents. Although it is known that the growth of osteosarcoma relies on oxidative phosphorylation for energy production, limited attention has been paid to exploring the potential of oxidative phosphorylation-related genes in predicting the prognosis of individuals suffering from osteosarcoma.
METHODS
All the data were retrieved from the UCSC Xena and GEO (GENE EXPRESSION OMNIBUS). Identification of the oxidative phosphorylation genes linked to the prognosis of individuals with osteosarcoma was done by means of univariate COX and LASSO regression analyses. Following that, patients were categorized into a high-risk group and a low-risk group as per the risk score determined by the identified oxidative phosphorylation genes. Furthermore, a comparison was made in terms of the survival and immune infiltration between both groups, and the prognostic model was established.
RESULTS
Five oxidative phosphorylation genes (ATP6V0D1, LHPP, COX6A2, MTHFD2, NDUFB9) associated with the prognosis of individuals with osteosarcoma were identified and the risk prognostic models were constructed. In the current research, the analysis of the ROC curves indicated a superior predictive accuracy exhibited by the risk model. The prognosis was adversely affected by immune infiltration in the high-risk group in comparison with the low-risk group. The function of the oxidative phosphorylation-related prognostic gene set was verified by GO and KEGG analysis. Furthermore, the link between oxidative phosphorylation-related genes and osteosarcoma immune infiltration was examined by GSEA analysis.
CONCLUSIONS
In this study, a prognostic model that demonstrated good predictive performance was constructed. Additionally, this study highlighted a correlation between oxidative phosphorylation-related genes and immune infiltration.
Topics: Humans; Adolescent; Oxidative Phosphorylation; Osteosarcoma; Prognosis; ROC Curve; Bone Neoplasms
PubMed: 38506898
DOI: 10.18632/aging.205650