Membrane potential respiratory inhibition

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. 

Stress Is Sensed by BH3-only Proteins. —> BH3-only proteins inhibit anti-apoptotic Bcl-2 proteins. Bax/Bak pore is formed. —> Cytochrome c and other apoptotic proteins are released from mitochondria. - They activate caspases. -> Caspases cleave the complex I subunit of the respiratory chain. -> It causes loss of membrane potential and generates ROS. - ROS modulates and open PTP and activates BH3-only proteins. 

Fig. 10.6. The effect of respiration and membrane potential (Ai )) on Cl permeation in brown adipose tissue mitochondria. When brown fat mitochondria were incubated in KCl in the presence of the ionophore, nigericin, they swelled (A, B). If a respiratory substrate (here G-3-P glycerol-3-phosphate) was added to the expanded mitochondria, they contracted, and this contraction ceased immediately and swelling was reintroduced if azide (NaNj) and an uncoupler (FCCP) were added (Fig. A). The passive halide ion permeability can be inhibited by GDP (cf.. Fig. 10.5), but respiration-driven contraction in KCl-expanded mitochondria was only partially inhibited by the presence of GDP (Fig. B) if again azide and uncoupler were added during the contraction, the mitochondria did not swell, indicating that the thermogenin channel was closed by GDP. This behaviour can partly be explained by the fact that the Cl permeation is driven by the membrane potential. Indeed, when, under similar conditions, the rate of contraction was plotted as a function of the membrane potential, it was seen that the rate was membrane potential dependent. It should, however, he noted that at low membrane potentials GDP nearly totally abolished the Cl permeation but when the membrane potential was increased above 30 mV, the inhibitory effect of GDP was apparently partially lost. The basis for this phenomenon is not understood it is not even known if there is a lower affinity of thermogenin for GDP in the energized membrane, as measurements of GDP affinities always refer to the non-energized situation. (Adapted from Nicholls et al. [27] (A, B) and Nicholls [94] (C).)...

ATP transport out of the mitochondrial matrix and ADP transport into the matrix are favored. This Al P—ADP exchange is energetically expensive about a quarter of the energy yield from electron transfer by the respiratory chain is consumed to regenerate the membrane potential that is tapped by this exchange process. The inhibition of this process leads to the subsequent inhibition of cellular respiration as well (p. 534). 

Fig. 16 Effects of amiodarone, perhexiline, and diethylaminoethoxyhexestrol (DEAEH) on mitochondrial function. After crossing the outer membrane, the uncharged secondary or tertiary amine (A) of amiodarone, perhexiline, or diethylaminoethoxyhexestrol (DEAEH) is protonated in the acidic intermembrane space. The positively charged molecule (AH ) is then electrophoretically pushed by the mitochondrial membrane potential into the matrix. High intramitochondrial concentrations inhibit both B-oxidation (causing steatosis) and oxidative phosphorylation, thus causing the accumulation of electrons in the respiratory chain and increasing the mitochondrial formation of ROS. The latter oxidize fat deposits, causing lipid peroxidation, which, together with ROS-induced cytokine production, could cause steatohepatitis.

Chromophores which are non-toxic at low concentrations may become potent inhibitors if they are concentrated in specific compartments. Cyanine dyes severely inhibit respiration at site 1 of the mitochondrial respiratory chain, providing that the inner mitochondrial membrane potential is substantial (inside negative) (18). In living cells, the irmer mitochondrial membrane potential is about 180 mV and the plasma membrane potential is about 60 mV (both inside negative), and extracellular csranine at 10" m is at electrochemical eqrrilibrium with mitochondrial cyanine when the latter reaches 10 m. Very low concentrations of cyanines may thus adversely affect cellular respiration and energy dependent processes (18). 

This combination of activities of Plnronic in MDR cells is due to the amphiphilic surfactant architecture of the block copolymer molecules, which can incorporate into cellular membranes resulting in changes in membrane permeability, membrane potential, and membrane transport of various compounds. The likely targets of Plmonic effects are the cell plasma membrane (where Pgp is localized) and the mitochondria membrane, where Plnronic affects normal functioning of the drug efflux transporters and respiratory chain, respectively [28,32]. Selected Pluronics, which can translocate inside the cell and thus affect intracellular compartments, in particular mitochondria, are the most efficacious modulators in both Pgp inhibition and ATP depletion [28]. 

The electrochemical potential difFetence across the membrane, once established as a tesult of proton translocation, inhibits further transport of teducing equivalents through the respiratory chain unless discharged by back-translocation of protons across the membtane through the vectorial ATP synthase. This in turn depends on availability of ADP and Pj. 

After initial experiments demonstrating that the antiserum was capable of completely inhibiting the binding of [ H]PbTx-3 to its receptor site in rat brain membranes (Figure 9), we began studies designed to evaluate potential of the antiserum for prophylaxis and treatment of brevetoxin intoxication (34). The tethered rat model was used, and surgical implantations were identical to those described above. Heart rate, core and peripheral body temperatures, lead VIO ECG, and arterial blood pressure were monitored continuously. Respiratory rate was recorded each 5 min for the first 3 hr, then each 15 min until 6 hr. 

In order to maximise the toxic potential of their venoms, many snakes have several toxins in their venoms which act by different biochemical mechanisms. This is an ingenious ploy which means that more than one of the bod/s vital systems is hit by the venom so making death more certain than if only one were hit. The Black Mamba is an excellent example of a snake with multiple toxic components in its venom. In addition to the fasciculins. Mamba venom has dendrotoxins which inhibit neurotransmission by blocking the exchange of + and - ions across the neuronal membrane. This prevents passage of the nerve impulse. If the impulse is en route to the big toe the toe will be paralysed — this is certainly not life-threatening. However, if the impulse is to the pulmonary muscles, respiratory failure and death will result. The dendrotoxins from the Black Mamba are very much less toxic than the fasciculins (it would take 1.6 g to kill a person), however the combined effect of the two toxins is far more toxic than the toxicities of the individual components (this is termed synergy) which is why the Black Mamba is lethal to humans. 

Membrane-depressant (quinidine-like) effects cause myocardial depression and cardiac conduction disturbances by inhibition of the fast sodium channel that initiates the cardiac cell action potential. Metabolic or respiratory acidosis may contribute to cardiotoxicity by further inhibiting the fast sodium channel. 

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