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Molecules (Basel, Switzerland) Nov 2019Diet, particularly the Mediterranean diet, has been considered as a protective factor against the development of cardiovascular diseases, the main cause of death in the... (Review)
Review
Diet, particularly the Mediterranean diet, has been considered as a protective factor against the development of cardiovascular diseases, the main cause of death in the world. Aging is one of the major risk factors for cardiovascular diseases, which have an oxidative pathophysiological component, being the mitochondria one of the key organelles in the regulation of oxidative stress. Certain natural bioactive compounds have the ability to regulate oxidative phosphorylation, the production of reactive oxygen species and the expression of mitochondrial proteins; but their efficacy within the mitochondrial physiopathology of cardiovascular diseases has not been clarified yet. The following review has the purpose of evaluating several natural compounds with evidence of mitochondrial effect in cardiovascular disease models, ascertaining the main cellular mechanisms and their potential use as functional foods for prevention of cardiovascular disease and healthy aging.
Topics: Aging; Animals; Cardiovascular Diseases; Humans; Mitochondria; Oxidative Phosphorylation; Oxidative Stress; Phytochemicals; Reactive Oxygen Species
PubMed: 31766727
DOI: 10.3390/molecules24234259 -
Proceedings of the National Academy of... Apr 1979A stable free-radical polymeric derivative of prostaglandin B1 (PGBx) has been synthesized that exhibits regenerative effects on oxidative phosphorylation in aged...
A stable free-radical polymeric derivative of prostaglandin B1 (PGBx) has been synthesized that exhibits regenerative effects on oxidative phosphorylation in aged mitochondria. The molecular weights of the most active preparations fall between 2000 and 2600. PGBx is characterized by a single-line electron spin resonance spectrum that is stable at room temperature. PGBx restores phosphorylating ability and net ATP synthesis in isolated mitochondria aged for 4 days at 0 degrees C and protects against further degradation of phosphorylating activity when such aged mitochondria are preincubated at 28 degrees C in the absence of adenine nucleotide phosphate acceptors. This compound has been reported to exert beneficial effects in vivo in experimental pathological conditions, such as regional ischemia, in which the mitochondria of the ischemic region may have been damaged.
Topics: Adenosine Triphosphate; Animals; Free Radicals; Kinetics; Mitochondria, Liver; Oxidative Phosphorylation; Oxygen Consumption; Polymers; Prostaglandins; Prostaglandins B; Rats
PubMed: 287000
DOI: 10.1073/pnas.76.4.1598 -
Cancer Biology & Therapy Feb 2013The early observations by Dr Otto Warburg revealed that fundamentally metabolic differences exist between malignant tumor cells and adjacent normal cells. Many studies... (Review)
Review
The early observations by Dr Otto Warburg revealed that fundamentally metabolic differences exist between malignant tumor cells and adjacent normal cells. Many studies have further reported the relationship between altered cellular metabolism and therapeutic outcomes. These observations suggest that targeting the peculiar metabolic pathways in cancer might be an effective strategy for cancer therapy. In recent years, investigations have accelerated into how altered cellular metabolism promotes tumor survival and growth. This review highlights the current concepts of altered metabolism in cancer and the molecular targets involved in glycolysis, mitochondria and glutamine metabolism and discusses future perspective of cellular metabolism-based cancer treatment.
Topics: Antineoplastic Agents; Energy Metabolism; Glutamine; Glycolysis; Humans; Metabolic Networks and Pathways; Mitochondria; Neoplasms; Oxidative Phosphorylation
PubMed: 23192270
DOI: 10.4161/cbt.22958 -
Cell Reports Apr 2024Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and...
Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.
Topics: Animals; Humans; Mitochondria; Oxidative Phosphorylation; Mice; Oxidative Stress; Peptidoglycan; Mice, Inbred C57BL; Adenosine Triphosphate
PubMed: 38583150
DOI: 10.1016/j.celrep.2024.114067 -
Particle and Fibre Toxicology May 2021Although airborne fine particulate matter (PM) pollution has been demonstrated as an independent risk factor for pulmonary and cardiovascular diseases, their...
BACKGROUND
Although airborne fine particulate matter (PM) pollution has been demonstrated as an independent risk factor for pulmonary and cardiovascular diseases, their currently-available toxicological data is still far from sufficient to explain the cause-and-effect. Platelets can regulate a variety of physiological and pathological processes, and the epidemiological study has indicated a positive association between PM exposure and the increased number of circulative platelets. As one of the target organs for PM pollution, the lung has been found to be involved in the storage of platelet progenitor cells (i.e. megakaryocytes) and thrombopoiesis. Whether PM exposure influences thrombopoiesis or not is thus explored in the present study by investigating the differentiation of megakaryocytes upon PM treatment.
RESULTS
The results showed that PM exposure promoted the thrombopoiesis in an exposure concentration-dependent manner. PM exposure induced the megakaryocytic maturation and development by causing cell morphological changes, occurrence of DNA ploidy, and alteration in the expressions of biomarkers for platelet formation. The proteomics assay demonstrated that the main metabolic pathway regulating PM-incurred alteration of megakaryocytic maturation and thrombopoiesis was the mitochondrial oxidative phosphorylation (OXPHOS) process. Furthermore, airborne PM sample promoted-thrombopoiesis from megakaryocytes was related to particle size, but independent of sampling filters.
CONCLUSION
The findings for the first time unveil the potential perturbation of haze exposure in thrombopoiesis from megakaryocytes by regulating mitochondrial OXPHOS. The substantial evidence on haze particle-incurred hematotoxicity obtained herein provided new insights for assessing the hazardous health risks from PM pollution.
Topics: Blood Platelets; Megakaryocytes; Oxidative Phosphorylation; Particulate Matter; Thrombopoiesis
PubMed: 33985555
DOI: 10.1186/s12989-021-00411-4 -
American Journal of Physiology. Cell... Aug 2016
A high-resolution method for assessing cellular oxidative phosphorylation efficiency: bringing mitochondrial bioenergetics into focus. Focus on "Direct real-time quantification of mitochondrial oxidative phosphorylation efficiency in permeabilized skeletal muscle myofibers".
Topics: Energy Metabolism; Mitochondria; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Phosphorylation
PubMed: 27413172
DOI: 10.1152/ajpcell.00203.2016 -
Journal of Neuroscience Research Nov 2017Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have...
Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have 1,190 unique succinylation sites representing multiple metabolic pathways. Succinylation is sensitive to both increases and decreases of the NAD -dependent desuccinylase, SIRT5. Although the succinyl group for succinylation is derived from metabolism, the effects of systematic variation of metabolism on mitochondrial succinylation are not known. Changes in succinylation of mitochondrial proteins following variations in metabolism were compared against the mitochondrial redox state as estimated by the mitochondrial NAD /NADH ratio using fluorescent probes. The ratio was decreased by reduced glycolysis and/or glutathione depletion (iodoacetic acid; 2-deoxyglucose), depressed tricarboxylic acid cycle activity (carboxyethyl ester of succinyl phosphonate), and impairment of electron transport (antimycin) or ATP synthase (oligomycin), while uncouplers of oxidative phosphorylation (carbonyl cyanide m-chlorophenyl hydrazine or tyrphostin) increased the NAD /NADH ratio. All of the conditions decreased succinylation. In contrast, reducing the oxygen from 20% to 2.4% increased succinylation. The results demonstrate that succinylation varies with metabolic states, is not correlated to the mitochondrial NAD /NADH ratio, and may help coordinate the response to metabolic challenge.
Topics: Animals; Cell Line, Tumor; Deoxyglucose; Mice; Mitochondrial Proteins; NAD; Organophosphonates; Oxidation-Reduction; Oxidative Phosphorylation; Succinates; Succinic Acid
PubMed: 28631845
DOI: 10.1002/jnr.24103 -
Biochemistry Apr 2013Calcium is believed to regulate mitochondrial oxidative phosphorylation, thereby contributing to the maintenance of cellular energy homeostasis. Skeletal muscle, with an...
Calcium is believed to regulate mitochondrial oxidative phosphorylation, thereby contributing to the maintenance of cellular energy homeostasis. Skeletal muscle, with an energy conversion dynamic range of up to 100-fold, is an extreme case for evaluating the cellular balance of ATP production and consumption. This study examined the role of Ca(2+) in the entire oxidative phosphorylation reaction network in isolated skeletal muscle mitochondria and attempted to extrapolate these results back to the muscle, in vivo. Kinetic analysis was conducted to evaluate the dose-response effect of Ca(2+) on the maximal velocity of oxidative phosphorylation (V(maxO)) and the ADP affinity. Force-flow analysis evaluated the interplay between energetic driving forces and flux to determine the conductance, or effective activity, of individual steps within oxidative phosphorylation. Measured driving forces [extramitochondrial phosphorylation potential (ΔG(ATP)), membrane potential, and redox states of NADH and cytochromes b(H), b(L), c(1), c, and a,a(3)] were compared with flux (oxygen consumption) at 37 °C; 840 nM Ca(2+) generated an ~2-fold increase in V(maxO) with no change in ADP affinity (~43 μM). Force-flow analysis revealed that Ca(2+) activation of V(maxO) was distributed throughout the oxidative phosphorylation reaction sequence. Specifically, Ca(2+) increased the conductance of Complex IV (2.3-fold), Complexes I and III (2.2-fold), ATP production/transport (2.4-fold), and fuel transport/dehydrogenases (1.7-fold). These data support the notion that Ca(2+) activates the entire muscle oxidative phosphorylation cascade, while extrapolation of these data to the exercising muscle predicts a significant role of Ca(2+) in maintaining cellular energy homeostasis.
Topics: Adenosine Diphosphate; Animals; Calcium; Cell Respiration; Cytochromes; Dose-Response Relationship, Drug; In Vitro Techniques; Kinetics; Membrane Potential, Mitochondrial; Mitochondria, Muscle; Muscle, Skeletal; Oxidative Phosphorylation; Swine; Thermodynamics
PubMed: 23547908
DOI: 10.1021/bi3015983 -
The Journal of Biological Chemistry Feb 1997glut1 gene expression and glucose transport are stimulated in a variety of cells and tissues in response to hypoxia. glut1 is also up-regulated by inhibitors of...
glut1 gene expression and glucose transport are stimulated in a variety of cells and tissues in response to hypoxia. glut1 is also up-regulated by inhibitors of oxidative phosphorylation (such as azide) in the presence of oxygen. Here, we test the hypothesis that hypoxia stimulates glut1 gene expression independent of its inhibitory effect on oxidative phosphorylation. We examined the effect of cobalt chloride, a known stimulator of genes responsive to reduced oxygen concentration per se, on GLUT1 expression under normoxic conditions and compared the results with the response to azide. Exposure of a rat liver cell line (Clone 9) to 250 microM cobalt chloride increases GLUT1 mRNA content, which becomes evident at 2 h, reaches a maximal value of approximately 12-fold at 8 h, and remains elevated at approximately 8-fold at 24 h. GLUT1 mRNA was the only GLUT isoform expressed in control cells and in cells exposed to cobalt chloride or azide. The induction of GLUT1 mRNA by cobalt chloride is associated with a approximately 10-fold stimulation of cytochalasin B-inhibitable 3-O-methyl-D-glucose transport at 24 h. In contrast to the rapid decrease in cell ATP levels and the stimulation of glucose transport in response to azide, cell ATP content and glucose transport remained unaltered during the initial 1-h period of exposure to cobalt chloride. The effect of cobalt chloride on GLUT1 mRNA content is mimicked by Ni(II) or Mn(II) but not by Fe(II). Employing actinomycin D, we found no increase in the approximately 1.5-h half-life of GLUT1 mRNA in cobalt chloride-treated cells, suggesting that the effect of cobalt chloride on GLUT1 mRNA content is largely mediated at the transcriptional level; in contrast, GLUT1 mRNA half-life increased to >8 h in azide-treated cells. In transient transfections we found that approximately 6 kilobase pairs (kbp) of 5'-flanking region of the rat glut1 promoter confers both cobalt chloride- and azide-inducibility to a reporter gene. Deletion of approximately 2, 500 base pairs (bp) from the 5' end of the approximately 6-kbp DNA fragment results in a reduction of the response to cobalt chloride and a complete loss of the response to azide. A 666-bp DNA segment located approximately 6.0 kbp upstream of the transcription start site was found to be necessary for the increase in reporter gene expression in response to azide, whereas a 480-bp segment located at approximately -3.5 kbp mediated the response to cobalt chloride. The 480-bp segment is highly homologous to the previously reported mouse glut1 enhancer and contains several potential regulatory elements, including a hypoxia-inducible element; an additional hypoxia-inducible element is present in the 666-bp segment. Our results suggest that glut1 gene expression is regulated in a dual fashion by hypoxia per se and in response to inhibition of oxidative phosphorylation.
Topics: 3T3 Cells; Animals; Anisomycin; Azides; Base Sequence; Cobalt; Dactinomycin; Gene Expression Regulation; Glucose Transporter Type 1; Mice; Molecular Sequence Data; Monosaccharide Transport Proteins; Oxidative Phosphorylation; Oxygen; Promoter Regions, Genetic; RNA, Messenger; Rats
PubMed: 9038162
DOI: 10.1074/jbc.272.9.5555 -
Toxins Aug 2021Patulin (PAT) belongs to the family of food-borne mycotoxins. Our previous studies revealed that PAT caused cytotoxicity in human embryonic kidney cells (HEK293). In the...
Patulin (PAT) belongs to the family of food-borne mycotoxins. Our previous studies revealed that PAT caused cytotoxicity in human embryonic kidney cells (HEK293). In the present research, we systematically explored the detailed mechanism of ROS production and ROS clearance in PAT-induced HEK293 cell apoptosis. Results showed that PAT treatment (2.5, 5, 7.5, 10 μM) for 10 h could regulate the expression of genes and proteins involved in the mitochondrial respiratory chain complex, resulting in dysfunction of mitochondrial oxidative phosphorylation and induction of ROS overproduction. We further investigated the role of -acetylcysteine (NAC), an ROS scavenger, in promoting the survival of PAT-treated HEK293 cells. NAC improves PAT-induced apoptosis of HEK293 cells by clearing excess ROS, modulating the expression of mitochondrial respiratory chain complex genes and proteins, and maintaining normal mitochondrial function. In addition, NAC protects the activity of antioxidant enzymes, maintains normal GSH content, and relieves oxidative damage. Additionally, 4 mM NAC alleviated 7.5 μM PAT-mediated apoptosis through the caspase pathway in HEK293 cells. In summary, our study demonstrated that ROS is significant in PAT-mediated cytotoxicity, which provides valuable insight into the management of PAT-associated health issues.
Topics: Acetylcysteine; Apoptosis; Cells, Cultured; HEK293 Cells; Humans; Metabolic Networks and Pathways; Mitochondria; Mycotoxins; Oxidative Phosphorylation; Oxidative Stress; Patulin; Reactive Oxygen Species
PubMed: 34564600
DOI: 10.3390/toxins13090595