TCMS inhibits ATP synthesis in mitochondria: A systematic analysis of the inhibitory mechanism (original) (raw)
Related papers
2007
The interactions of the antifouling compound TCMS (2,3,5,6-tetrachloro-4-methylsulphonyl pyridine) with rat liver mitochondria have been investigated. The results indicate that the compound inhibits ATP synthesis. Further investigations regarding the ATP synthesis mechanism suggest that TCMS inhibits succinic dehydrogenase of the mitochondrial respiratory chain. As the respiratory chain is similar in all living organisms, it can be concluded that the toxic effect of TCMS most likely depend on the different bioavailability of the compound and on the different importance of mitochondria in the ATP production in the animal species.
Annals of the New York Academy of Sciences, 1999
Activation of the apoptotic program by cytochrome c and apoptosis-inducing factor (AIF) requires release of these intermembrane proteins into the cytosol, and the mechanism(s) by which this occurs is the subject of intense investigation. One of the most studied targets is the mitochondrial permeability transition (PT). The sudden increase of permeability of the inner membrane to solutes has been extensively studied. 1 A specific issue is whether or not a mitochondrial PT is a requisite for the release of apoptogenic proteins. This is an issue that has generated conflicting results and has become a major controversy in the literature. A specific, PT-independent release mechanism has been proposed based on the finding that cytochrome c release occurs without measurable decrease of the mitochondrial membrane potential (∆Ψ m ). 2-4 This point remains very controversial. Others have reported that cytochrome c release matches membrane depolarization, 5 and that it is mediated by a PT. 6,7 This has been indicated as the major determinant of AIF release. Many of these studies were performed with the "fixable" probe chloromethyltetramethyl rosamine (CMTMRos) to monitor changes of ∆Ψ m in situ. We have carried out a characterization of the interactions of this probe with mitochondria.
Imidacloprid affects rat liver mitochondrial bioenergetics by inhibiting FoF1-ATP synthase activity
Journal of Toxicology and Environmental Health, Part A
Imidacloprid (IMD) is a neonicotinoid insecticide widely used in crops, pets, and on farm animals for pest control. Several studies were conducted examining the adverse effects of IMD on animals often exhibiting hepatic damage. The aim of this study was to determine the effects of IMD on bioenergetics of mitochondria isolated from rat liver. Imidacloprid (50-200 µM) produced a concentration-dependent decrease in oxygen consumption and ATP production without markedly affecting mitochondrial membrane potential (MMP). Oxygen consumption experiments showed that IMD did not significantly affect the respiratory chain, and this was similar to findings with oligomycin and carboxyatractyloside, suggesting a direct action on F o F 1-ATP synthase and/or the adenine nucleotide translocator (ANT). Imidacloprid inhibited F o F 1-ATP synthase activity only in disrupted mitochondria and induced a partial inhibition of ADP-stimulated depolarization of the MMP. Our results indicate that IMD interacts specifically with F o F 1-ATP synthase resulting in functional inhibition of the enzyme with consequent impairment of mitochondrial bioenergetics. These effects of IMD on mitochondrial bioenergetics may be related to adverse effects of this insecticide on the liver.
Amine fluorescamine compounds inhibit oxidative phosphorylation in rat liver mitochondria
Archives of Biochemistry and Biophysics, 1984
The reaction of fluorescamine with ammonia, benzylamine, o,p-dimethylbenzylamine, 2-phenylethylamine, p-aminobenzoic acid, and the mycosamine-containing macrolide antibiotic, amphotericin B, yield compounds which induce significant effects on mitochondrial activities. From their effects on energy-yielding processes which lead to transmembranous proton movements, the compounds may be divided into three classes. While all modifiers significantly inhibit proton movement induced by both ATP hydrolysis and electron transfer in mitochondria, their influence on the primary energy yielding steps are quite different. Class I modifiers, e.g., the compound made from amphotericin B, inhibit electron transfer but have no effect on the Pi release associated with ATP hydrolysis. Class II modifiers, e.g., the compound made from benzylamine, inhibit respiration but stimulate Pi release. Class III modifiers, e.g., the compound made from p-aminobenzoic acid, on the other hand, only slightly increase Pi release but have no effect on redox reactions. These and other effects of the modifiers are taken to mean that the proton movements and their associated energy-yielding processes are only linked indirectly. The effects of the modifiers on State 3 mitochondrial activities were also investigated. Although all the modifiers decrease the rates of both State 3 respiration and its coupled ATP synthesis, the efficiency of energy conversion measured by the P/O ratio remains unaltered.
European Journal of Medicinal Chemistry, 2010
A series of 2-(3-aryl-1-oxo-2-propenyl)-3-methylquinoxaline-1,4-dioxides 1a-l and 2-acetyl-3methyl-quinoxaline-1,4-dioxide 2 were evaluated against Mycobacterium tuberculosis H 37 Rv. With the exception of the 4-nitro analog 1k, significant antitubercular potencies were observed in series 1 and 2 which have IC 50 values in the range of 1-23 μM. Negative correlations were noted between the IC 50 values of 1a-j, l towards M. tuberculosis and both the σ and π constants of the substituents in the benzylidene aryl ring. In particular, 1h emerged as a lead compound having IC 50 and IC 90 figures of 1.03 μM and 1.53 μM, respectively. This molecule affected respiration in rat liver mitochondria which is likely one way that 1h and the bioactive analogs exert their antitubercular properties. The quinoxaline 2, which lacks an α,β-unsaturated group, has no effect on mitochondrial respiration using concentrations which inhibit the growth of M. tuberculosis.
PLOS ONE, 2016
Methyltriphenylphosphonium (TPMP) salts have been widely used to measure the mitochondrial membrane potential and the triphenylphosphonium (TPP +) moiety has been attached to many bioactive compounds including antioxidants to target them into mitochondria thanks to their high affinity to accumulate in the mitochondrial matrix. The adverse effects of these compounds on cellular metabolism have been insufficiently studied and are still poorly understood. Micromolar concentrations of TPMP cause a progressive inhibition of cellular respiration in adherent cells without a marked effect on mitochondrial coupling. In permeabilized cells the inhibition was limited to NADH-linked respiration. We found a mixed inhibition of the Krebs cycle enzyme 2-oxoglutarate dehydrogenase complex (OGDHC) with an estimated IC 50 3.93 [3.70-4.17] mM, which is pharmacologically plausible since it corresponds to micromolar extracellular concentrations. Increasing the lipophilic character of the used TPP + compound further potentiates the inhibition of OGDHC activity. This effect of TPMP on the Krebs cycle ought to be taken into account when interpreting observations on cells and mitochondria in the presence of TPP + derivatives. Compounds based on or similar to TPP + derivatives may also be used to alter OGDHC activity for experimental or therapeutic purposes.
Environmental Toxicology and Pharmacology, 2015
Fipronil is an insecticide extensively used to control pests in crops and animals. There are relates of poisoning due to exposure of fipronil in mammals and the liver has been suggested as potential target. In this study, we evaluated the effects of fipronil and its metabolites sulfone and desulfinyl on the bioenergetics, reactive oxygen species (ROS) production and calcium efflux from mitochondria isolated from rat liver. Fipronil (5-25 M) inhibited state-3 respiration in mitochondria energized with glutamate plus malate, substrates of complex I of the respiratory chain and decreased the mitochondrial membrane potential resulting in inhibition of ATP synthesis. Fipronil also caused uncoupling in succinate-energized mitochondria and calcium efflux. The metabolites sulfone and desulfinyl also acted as mitochondrial inhibitors and uncouplers and caused calcium efflux, but with different potencies, being the sulfone the more potent one. These effects of fipronil and its metabolites on mitochondrial bioenergetics and calcium homeostasis may be related to toxic effects of the insecticide in the liver.