Respiration oxidative phosphorylation

Aminophenol is a selective nephrotoxic agent and intermpts proximal tubular function (121,122). Disagreement exists concerning the nephrotoxity of the other isomers although they are not as potent as 4-aminophenol (123,124). Respiration, oxidative phosphorylation, and ATPase activity are inhibited in rat kidney mitochondria (125). The aminophenols and their derivatives are inhibitors of 5-Hpoxygenase (126) and prostaglandin synthetase... 

Energy Efficiency of Aerobic Respiration (Oxidative Phosphorylation)... 

Like most bacteria, the Microtox strain has many metabolic pathways which function in respiration, oxidative phosphorylation, osmotic stabilization, and transport of chemicals and nutrients into and out of the cell, and which are located within or near the cytoplasmic membrane. The luciferase pathway [9], which functions as a shunt for electrons directly to oxygen at the level of reduced flavin mono-nucleotide, is also located within the cell membrane complex. This, coupled with lack of membrane-aided compartmentalization of internal functions, gives many target sites at or near the cytoplasmic membrane. These factors all contribute to a rapid response of the organisms to a broad spectrum of toxic substances. 

It is well established that most of the known anaerobic prokaryotes perform oxidative phosphorylation without O2. Depending on the species and the metabolic conditions, these bacteria may use a large variety of inorganic (e.g., nitrate, nitrite, sulfate, thiosulfate, elemental sulfm, polysulfide sulfur) or organic compounds (e.g., fumarate, dimethylsulfoxide, trimethylamine-A -oxide, vinyl- or arylchlorides) as terminal electron acceptor instead of oxygen. The redox reactions with these acceptors are catalyzed by membrane-integrated electron transport chains and are coupled to the generation of an electrochemical proton potential (Ap) across the membrane. Oxidative phosphorylation in the absence of O2 is also termed anaerobic respiration . Oxidative phosphorylation with elemental sulfur is called sulfm respiration . Oxidative phosphorylation with polysulfide sulfur is called polysulfide respiration . 

There is a growing recognition that mitochondria play a central role in apoptosis [10,11], Mitochondria-dependent apoptotic pathways are responsive to intrinsic proapoptotic stimuli that cause perturbations in the intracellular environment, particularly oxidative stress. In addition, other apoptotic signaling pathways appear to converge onto the mitochondria. This raises the question of whether flavonoids may modulate events upstream or downstream of the mitochondria-dependent apoptotic cascade, in addition to their potential effect on mitochondrial respiration, oxidative phosphorylation, and oxyradical generation (as discussed earlier). 

Cancer cells generally use glycolysis rather than respiration (oxidative phosphorylation) for energy (the Warburg effect), as a result of hypoxia that exists in tumors and damaged mitochondria. Usually dangerously damaged cells kill themselves via apoptosis, a mechanism of self-destruction that involves mitochondria, but this mechanism fails in cancer cells. 

The modes of action for niclosamide are interference with respiration and blockade of glucose uptake. It uncouples oxidative phosphorylation in both mammalian and taenioid mitochondria (22,23), inhibiting the anaerobic incorporation of inorganic phosphate into adenosine triphosphate (ATP). Tapeworms are very sensitive to niclosamide because they depend on the anaerobic metaboHsm of carbohydrates as their major source of energy. Niclosamide has selective toxicity for the parasites as compared with the host because Httle niclosamide is absorbed from the gastrointestinal tract. Adverse effects are uncommon, except for occasional gastrointestinal upset. 

Many inhibitors of substrate oxidations, substrate transport, electron transport, and ATP synthesis are known including many well-known toxins (see Sherratt, 1981 Harold, 1986 Nicholls and Ferguson, 1992). These are not discussed here except to mention specific uncouplers of oxidative phosphorylation. Classic uncouplers such as 2,4-dinitrophenol have protonated and unprotonated forms, both of which are lipid soluble and cross the inner mitochondrial membrane discharging the proton gradient. This prevents ATP synthesis and stimulates respiration. 

Nucleic acids are not the only biomolecules susceptible to damage by carotenoid degradation products. Degradation products of (3-carotene have been shown to induce damage to mitochondrial proteins and lipids (Siems et al., 2002), to inhibit mitochondrial respiration in isolated rat liver mitochondria, and to induce uncoupling of oxidative phosphorylation (Siems et al., 2005). Moreover, it has been demonstrated that the degradation products of (3-carotene, which include various aldehydes, are more potent inhibitors of Na-K ATPase than 4-hydroxynonenal, an aldehydic product of lipid peroxidaton (Siems et al., 2000). 

Answer C. The toxic agent (example, 2,4-dinitrophenol) would uncouple oxidative phosphorylation, leading to a fall in ATP levels, increased respiration, and increased substrate utilization. 

Mitochondria, which are cytoplasmic organelles involved in cellular respiration, have their own chromosome, which contains 16,569 DNA base pairs (bp) arranged in a drcalar molecule. This DNA encodes 13 proteins that are subunits of complexes in the electron transport and oxidative phosphorylation processes (see Section 1, Chapter 13). In addition, mitochondrial DNA encodes 22 transfer RNAs and two ribosomal RNAs. 

Other work has indicated that chlordane and heptachlor are energy transfer inhibitors as evidenced by marked decreases in oxidative phosphorylation of rat hepatic mitochondria following in vitro incubation of the mitochondria with the pesticides (Ogata et al. 1989). Interestingly, even though heptachlor epoxide is more toxic than either chlordane or heptachlor in tests of general toxicity, it was less effective in inhibiting mitochondrial respiration. 

The metabolic machinery responsible for the heterotrophic respiration reactions is contained in specialized organelles called mitochondria. These reactions occur in three stages (1) glycolysis, (2) the Krebs or tricarboxylic acid cycle, and (3) the process of oxidative phosphorylation also known as the electron transport chain. As illustrated in... 

Uncoupling of oxidative phosphorylation from respiration in brown adipose tissue and possibly other tissues (e.g. in muscle) (Chapter 9). 

Toxicology. 2,4-Dichlorophenol (2,4-DCP) is an uncoupler of oxidative phosphorylation toxic manifestations include central nervous system depression followed by increased respiration, hyperthermia, increased blood pressure, progressive weakness, and cyanosis. 

Phenolic compounds naturally occurring in plants have induced many physiological responses that duplicate those reported for ozone and/or peroxyacetylnitrate (PAN). Chlorogenic acid is a competitive inhibitor of lAA-oxidase (35) and plant growth is adversely affected by increased concentrations of auxins (36). Concentrations of chlorogenic acid are increased in tobacco tissue exposed to ozone ( ) Phenols inhibit ATP synthesis (37), oxidative phosphorylation ( ) and SH enzyme activity (27) they increase respiration (38), reduce CO2 fixation (22), modify both membrane permeability (40) and oxidation rate of reduced NADH... 

Intact tobacco plants were exposed to 0.60-0.70 yl/1 ozone for 1 hr mitochondria isolated from visibly injured tissue demonstrated an inhibition of oxidative phosphorylation in conjunction with an increase in respiration (6). However, when detached tobacco leaves were fumigated with 1.0 yl/1 ozone for 1-5 hr, the mitochondria extracted from the tissue prior to s3rmptom development exhibited reduced oxygen uptake and reduced oxidative phosphorylation (7 ). In an experiment of similar design when ozone was bubbled through a solution of isolated mitochondria, both respiration and oxidative phosphorylation were reduced (7 ). 

In addition to the above-mentioned properties, the piperidine alkaloids exhibit a wide range of physiological activities. Thus, neuromuscular transmission is shown to be blocked by Ic and Id (72). Mitochondrial respiration is decreased and oxidative phosphorylation uncoupled at low concentrations of Ig (75), which, in addition to cw-6-methyl-2-(cw-6 - -pentadecenyl)piperidine (2c), inhibits the reactions of the Na+, K + -ATPase (14). 

These studies demonstrate the general mechanism of synchronization of biochemical systems, which I expect to be operative in even more complex systems, such as the mitochondrial respiration or the periodic activity of the slime mold Dictyostelium discoideum. As shown in a number of laboratories under suitable conditions mitochondrial respiration can break into self-sustained oscillations of ATP and ADP, NADH, cytochromes, and oxygen uptake as well as various ion transport and proton transport functions. It is important to note that mitochondrial respiration and oxidative phosphorylation under conditions of oscillations is open for the source, namely, oxygen, as well as with respect to a number of sink reactions producing water, carbon dioxide, and heat. 

Dinitrophenols had been used as insecticides since 1892 but it was not until the 1930s that their value as herbicides was discovered and 4,6-dinitro-o-cresol (DNOC) was introduced. The trouble with dinitrophenols was their toxicity to all living organisms that respire. Their mode of action is through the uncoupling of oxidative phosphorylation, an effect that leads to a rapid death of any organism that comes into contact with the chemical, including the operator. 

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