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Outdoor Air Pollution
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Mitochondria have a proteome of approximately 1500 proteins.221 Nearly 1000 of these proteins have catalytic functions in cell metabolism such as citrate synthase or malate dehydrogenase. Under normal physiologic conditions, the concentrations of thousands of nutrients and metabolic substrates in mitochondria are closely governed by the collective kinetic constants (Km, Kcat, V, Hill coefficient, etc.) of all the enzymes responsible for transforming those metabolites. This has recently been computationally modeled in the Recon 1 and BiGG reconstructions of cell and organ metabolism.222,223 Only the primary structure of an enzyme is genetically determined. The activity of an enzyme at any instant in time is determined by ambient metabolic conditions. The environmental triggering agents, for example, the Km of citrate synthase for oxaloacetate is approximately 2 μM, but the enzyme is allosterically inhibited by ATP, NADH, acetyl-CoA, palmitoyl-CoA, and the product citric acid so the rate of converting oxaloacetate to citrate is changing minute to minute according to the condition of the cell.224 When the concentrations of substrates are perturbed by viral or microbial infection, disease, toxin, or nutritional excess, mitochondria sense this as a metabolic mismatch between the optimum concentration of those metabolites for a given tissue and the actual concentration. Thus the chemically sensitive patient due to its varied metabolism responds differently at different times. At times, they have more resistance and other times are very vulnerable. This function at times makes treatment doses of antigens and nutrients difficult to deliver due to the need for varying doses. Of course, medications, nutrients, and interdermal neutralization at varying times are fixed doses and may not function at times of crises unless they are primed over weeks and months when the organism is stable.
Distribution and Biological Functions of Pyruvate Carboxylase in Nature
Published in D. B. Keech, J. C. Wallace, Pyruvate Carboxylase, 2018
The weight of evidence favors an exclusively mitochondrial location for pyruvate carboxylase in most vertebrate tissues (see Section V.R). However, when Haarasilta and Taskinen354,358 used sucrose density gradient centrifugation to fractionate yeast spheroplast lysates, they found 96% of the recovered pyruvate carboxylase activity in fractions of density less than 1.055 g/cm3. Thus, pyruvate carboxylase was sedimented along with PEP carboxykinase fEC 4.1.1.32], hexosediphosphatase [EC 3.1.3.11], and isocitrate lyase [EC 4.1.3.1], and was clearly separated from the mitochondrial membrane marker enzyme, cytochrome c-oxidase, all of which was found in fractions of density 1.15 g/cm3 or above. Although it is evident from the variation in the amount of sedimentable malate dehydrogenase and catalase in different fractionations (see Figure 3) that some breakage of mitochondria and microbodies has occurred, it is not possible to evaluate accurately the recovery of intact mitochondria and microbodies, since the proportion of malate dehydrogenase in mitchondria and of catalase in microbodies in yeast in vivo is not known. To this end it would have been of greater value to have used citrate synthase [EC 4.1.3.7] as a marker enzyme of the mitochondrial matrix since in all other situations that is its exclusive location. Malate dehydrogenase, on the other hand, is well known64 to have two distinct isoenzymes, one in the mito-chondrial matrix and the other in the cytosol. Nevertheless, had pyruvate carboxylase been entirely of mitochondrial origin it seems unlikely that only 3 to 4% of its total activity would remain within the mitochondria when at least 10% (Figure 3B) and up to 25% (Figure 3A) of the total (i.e., cytoplasmic plus mitochondrial) malate dehydrogenase activity was coincident with the cytochrome c oxidase activity. Hence, it seems that pyruvate carboxylase activity has a mainly cytosoiic location in yeast. This must have important implications for the organization of lipid and amino acid biosynthesis in this organism, and raises the question of how the anaplerotic requirements of yeast mitochondria are fulfilled.
Brain Metabolism During Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
From animal studies, it may be deduced that in brain cortex and in some subcortical nuclei glucose consumption diminishes from development to adulthood, but not further with advanced age.74–76 At the cellular level, a moderate but steady decline in the concentration of glycolytic compounds was found from development to senescence. However, the diminution was not evenly distributed with respect to the different periods of life. Glucose and fructose-l,6-diphosphate, and ATP, too, decreased the most from development to adulthood, whereas pyruvate and creatine phosphate fell most from adulthood to senescence.77 The changes in glycolytic compounds are associated with age-related reductions in the activities of the enzymes hexokinase and phosphofructokinase, controlling glycolytic flux.78,79 On the other hand, only slight variations are found in the oxidation processes of the tricarboxylic acid cycle and the respiratory chain with aging. The decrease in malate concentration found in senescent rats may be consistent with the reduced activity of malate dehydrogenase,77,80 indicating diminished tricarboxylic acid cycle activity. Otherwise, no age-related changes were reported in the enzyme activities of pyruvate dehydrogenase complex (active and total), citrate synthase, NAD+-isocitrate dehydrogenase, fumarase, and NAD+ malate dehydrogenase,81,82 although the finding about NAD+-isocitrate dehydrogenase was inconsistent.83 Studies on cytochrome a, a3 as the final member of substrate oxidation that reacts directly with molecular oxygen revealed no aged-related changes.84 However, in cerebral cortex of rats, oxygen consumption was found to decrease gradually with age85 and 14CO2 production diminished by around 30% in senescence. The neurotransmitters that derive from the breakdown of glucose in the brain also show reduced concentrations with aging. Acetylcholine synthesis declined to 65% in senescence as compared to young adulthood; acetylcholine release dropped to around 25% in the same study,86 and to around 50% in another.87 The number of muscarinic receptors in the dorsal hippocampus was reduced by 22% in aged rats.88 In total, these findings are indicative of the reduced capacity of the acetylcholinergic system with age.
Pyroptosis in neurodegenerative diseases: What lies beneath the tip of the iceberg?
Published in International Reviews of Immunology, 2023
Mengli Yue, Li Xiao, Rui Yan, Xinyi Li, Wei Yang
Since researchers found that glycolysis pathways could be exploited for cancer therapeutic purposes, the in-depth exploration of the key molecules in this pathway has never stopped [39]. α-Ketoglutarate (α-KG) serves as an essential metabolite in many physiological processes such as tricarboxylic acid (TCA) cycle, lipid biosynthesis, oxidative stress reduction, protein modification, cell death and so on. Recent study has uncovered its novel role in pyroptosis. Dimethyl α-Ketoglutarate (DM-α KG), a cell-permeable analog of α-KG, can penetrate the cell membrane and effectively induce tumor cell pyroptosis through DM-α-KG/L-2 hydroxyglutarate (L-2HG)/Reactive Oxygen Species (ROS)/Death Receptor-6 (DR6)/Caspase-8/GSDMC axis. In physiological state, metabolic enzyme malate dehydrogenase 1 (MDH1) has no function. While in an acidic environment, it can transform α-KG to L-2HG, which triggers the increase of ROS level in cells and induces the oxidative polymerization of DR6 on cell membrane. Then endocytosis occurs with receptosomes. Endocytic DR6 is activated through the recruitment of pro-caspase-8 to receptosomes mediated by Fas associated via death domain(FADD). At the same time, GSDMC is also recruited and cleaved by activated caspase-8 on receptosomes. Finally, the N-terminal GSDMC targets the cell membrane and leads to cell death by pore-formation [40].
Really does temperature reduction and norepinephrine have similar effects on the energy metabolism in rat brown adipose tissue?
Published in Archives of Physiology and Biochemistry, 2018
B. Sopeña, Z. López-Ibarra, A. J. López-Farré, N. de las Heras, S. Ballesteros, A. González-Cantalapiedra, V. Lahera, J. J. Zamorano-León
As previously we have reported (Modrego et al.2012, López-Ibarra et al.2015), proteins were separated on denaturing SDS-PAGE 15% (w/v) polyacrylamide gels by loading 20 μg/lane protein solubilised in Laemmli buffer containing 2-mercaptoethanol. After electrophoresis, proteins were blotted onto nitrocellulose membranes (Immobilion-P; Millipore, Billerica, MA), and then blocked overnight at 4 °C with 5% (w/v) albumin. Nitrocellulose membranes were then incubated with different antibodies against each of the aforementioned proteins. Indeed, CPT-I and CPT-II were determined using polyclonal antibodies (sc-20670 and sc-20526, respectively, dilution 1:1000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Mitochondrial malate dehydrogenase and lactate dehydrogenase were determined using monoclonal antibodies (sc-1666879 and sc-133123, dilution 1:1000, Santa Cruz Biotechnology, Inc., Santa Cruz, CA). UCP-1 was determined using a polyclonal antibody (ab23841 dilution 1:1000, Abcam, Cambridge, UK). The core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (MT-ND1), cytochrome c oxidase and mitochondrial F1 ATP synthase α-chain were determined using monoclonal antibodies (ab181848, Abcam, Cambridge, UK; sc-58613, Santa Cruz Biotechnology, Inc., Santa Cruz, CA; ab14705 Abcam, Cambridge, UK, respectively; dilution 1:1000). Nitrocellulose was also incubated with a monoclonal anti-β-actin antibody (A-5441, Sigma-Aldrich, St. Louis, MO, dilution 1:1500) used as loading control.
Protective effect of Argan oil on mitochondrial function and oxidative stress against acrylamide-induced liver and kidney injury in rats
Published in Biomarkers, 2020
Rahime Er, Birsen Aydın, Vedat Şekeroğlu, Zülal Atlı Şekeroğlu
Complex I and complex II activities were estimated by the method of Janssen et al. (2007). For determining the complex IV activity, firstly 1 mM ferrocytochrome C solution was prepared from ferricytochrome-C using sodium dithionate (Spinazzi et al.2012) and then its activity was estimated by the method of Trounce et al. (1996). Mitochondrial NADP+-dependent isocitrate dehydrogenase activity was estimated according to the method of Fatania et al. (1993). Alpha-ketoglutarate dehydrogenase (α-KGDH) activity was estimated according to the method of Lucas et al. (2003). Malate dehydrogenase (MDH) activity was determined according to the method of Gelpi et al. (1992).