Mitochondrial inhibition

In 1984, Hibbs, Taintor, and Vavrin reported that CAMs cause L1210 cells to lose up to 64% of their intracellular iron, and the time course of this release is similar to that of CAM-induced mitochondrial inhibition In 1986, Drapier and Hibbs " showed that aconitase (an iron-sulfur-containing enzyme (see Iron-Sulfur Proteins)) is also a target for CAM injury, and that the injured cells recover aconitase activity... 

Del Rio, P., Montiel, T., Chagoya, V., Massieu, L. (2007). Exacerbation of excitotoxic neuronal death induced during mitochondrial inhibition in vivo relation to energy imbalance or ATP depletion Neuroscience 146 1561-70. 

In vitro systems have been developed to try and understand the mechanism of action of maneb. In particular, the mechanism of toxicity of maneb on the central nervous system using synaptosomal and mitochondrial preparations from brain tissue has been utilized. These studies have shown that maneb has adverse effects on the dopaminergic system, via mechanisms that relate to mitochondrial inhibition and altered neurotransmitter uptake. The genotoxic, cytotoxic, and neurotoxic effects of maneb have been studied using a variety of primary cultures as well as cell lines, including human lymphocytes. As noted above, maneb has little mutagenic potential. 

If this sort of mitochondrial inhibition turns out to be generally the case, as we would predict, then the egg cells would be unable to provide all their own energy by respiration. This leads to a final predication from Allen that the follicle cells surrounding the developing egg should provide the egg with energy in the form of ATP. Whether or not this is true is unknown, but the morphological structure of the follicles suggests that it may well be. 

Our observations appear to be consistent with Landolt s findings, in which they indicated that acetogenins with the bis-adjacent THF ring or the bis-nonadjacent THF ring are about ten times more active than those with the mono-THF ring after a more complete research in screening 20 acetogenins by mitochondrial inhibition assay in 1995 [81]. 

This concluded an impressive and comprehensive SAR survey around the initial HTS hit through to a development candidate. Subsequent publications from the Merck group have indicated the compound to be hepatotoxic in predinical rat studies at elevated doses, implying a mechanism of mitochondrial inhibition and explaining the discontinuation of Merck A [58]. 

Propofol infusion syndrome Propofol infusion syndrome has been reported in children and adults after short-term high-dose propofol. It presents with variations of severe metabolic acidosis, rhabdomyolysis, myoglobinuria, cardiac failure, and death. The pathophysiology is unknown, but genetic predisposition, mitochondrial inhibition, and increases in serum free fatty acids are believed to play a role. Catecholamines and corticosteroids may act as triggering agents. 

III. Does Mitochondrial Inhibition Mimic Hypoxic Regulation of 02-Sensitive Voltage-Dependent Currents in Neonatal Chromaffin Cells ... 

P5C synthase Intestinal mucosa, Chinese hamster lung Mitochondrial Inhibited by ornithine, induced in probf-... 

Insects poisoned with rotenone exhibit a steady decline ia oxygen consumption and the iasecticide has been shown to have a specific action ia interfering with the electron transport iavolved ia the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD) by cytochrome b. Poisoning, therefore, inhibits the mitochondrial oxidation of Krebs-cycle iatermediates which is catalysed by NAD. 

Hydramethylnon [67485-29-4] is tetrabydro-5,5-dimetbyl-2-(1 H)-pyrimidinone [bis-l,5-(4-trifluoromethylphenyl)-3-penta-l,4-dienylidene] hydrazone (152) (mp 189°C). It is a slow-acting stomach poison used in baits and traps to control ants and cockroaches. Its mode of action is inhibition of mitochondrial electron transport. 

Two important pathways for catecholamine metaboHsm are 0-methylation by COMT, which is cytoplasmicaHy localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the fiver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in high concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the fiver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-37] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is relatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

Following the action of extraordinary stimulants (hypoxic hypoxia, hypoxia + hyperoxia, hypodynamia + hyperthermia), animals demonstrate an accumulation of malonic dialdehyde with a simultaneous fall of antiradical activity of the liver tissue. A preliminary introduction to rats of acetylene amine 3,4,5-tris(morpho-linopropynyl)-l-methylpyrazole 103 and also of tocopherol antioxidant and gutumine antihypoxant averts activation of the lipid peroxidation processes. The inhibition of peroxidation with this agent is mediated by stabilization of ly-zosomal and mitochondrial membranes. Unsaturated amines prevent destruction of the organelle membranes provoked by UV irradiation and incubation at 37°C (pH4.7)(78MIl). 

Atovaquone, a hydroxynaphthoquinone, selectively inhibits the respiratory chain of protozoan mitochondria at the cytochrome bcl complex (complex III) by mimicking the natural substrate, ubiquinone. Inhibition of cytochrome bcl disrupts the mitochondrial electron transfer chain and leads to a breakdown of the mitochondrial membrane potential. Atovaquone is effective against all parasite stages in humans, including the liver stages. 

BID is a member oftheBcl-2 gene family, which encode proteins that function either to promote apoptosis or to inhibit apoptosis as in the proteins derived from Bcl-2. These proteins can exist as monomers or they can dimerize. For example, if two promoting Bcl-2 family proteins dimerize then apoptosis will be greatly enhanced. Conversely, if dimerization of an inhibitory and promotor protein occurs, then the effects are cancelled out. The Bcl-2 family of proteins are localized to the outer mitochondrial or outer nuclear membranes. 

Coenzyme Qio (ubiquinone) is a coenzyme in the mitochondrial respiratoiy chain. It has a side chain made up of 10 isoprene units. Its synthesis can be inhibited by... 

---