Inhibition respiratory chain

The results of experiments to be described below appear to show that anoxia and cell poisons which inhibit respiratory chain phosphorylation stimulate uptake of glucose by muscle and that under suitable conditions respiration of fatty acids and ketone bodies can lead to inhibition of glucose uptake. Since fatty acids and ketone bodies are oxidized by mitochondria and since the effects of anoxia and of these cell poisons will be exerted principally on mitochondrial metabolism it seems reasonable to accept these findings as common evidence for a regulatory effect of mitochondrial metabolism on glucose uptake. It is recognized that this concept is provisional until such time as the mechanism of this regulation has been established. 

Figure 5.5 Respiratory chains in A. niger. SHAM = salicyl-hydroxamic acid Fp = flavoprotein -= inhibition x and y are unidentified components.

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. 

Barbiturates such as amobarbital inhibit NAD-hnked dehydrogenases by blocking the transfer from FeS to Q. At sufficient dosage, they are fatal in vivo. Antin cin A and dimercaprol inhibit the respiratory chain between cytochrome b and cytochrome c. The classic poisons H2S, carbon monoxide, and cyanide inhibit cytochrome oxidase and can therefore totally arrest respiration. Malonate is a competitive inhibitor of succinate dehydrogenase. 

Figure 12-7. Proposed sites of inhibition (0) of the respiratory chain by specific drugs, chemicals, and antibiotics. The sites that appear to support phosphorylation are indicated. BAL, dimercaprol. TTFA, an Fe-chelating agent. Complex I, NADHiubiquinone oxidoreductase complex II, succinate ubiquinone oxidoreductase complex III, ubiquinohferricytochrome c oxidoreductase complex IV, ferrocytochrome ctoxygen oxidoreductase. Other abbreviations as in Figure 12-4.

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. 

Many well-known poisons such as cyanide arrest respiration by inhibition of the respiratory chain. 

As described earlier, superoxide is a well-proven participant in apoptosis, and its role is tightly connected with the release of cytochrome c. It has been proposed that a switch from the normal four-electron reduction of dioxygen through mitochondrial respiratory chain to the one-electron reduction of dioxygen to superoxide can be an initial event in apoptosis development. This proposal was supported by experimental data. Thus, Petrosillo et al. [104] have shown that mitochondrial-produced oxygen radicals induced the dissociation of cytochrome c from bovine heart submitochondrial particles supposedly via cardiolipin peroxidation. Similarly, it has been found [105] that superoxide elicited rapid cytochrome c release in permeabilized HepG2 cells. In contrast, it was also suggested [106] that it is the release of cytochrome c that inhibits mitochondrial respiration and stimulates superoxide production. 

Cytochrome c oxidase (an enzyme in the mitochondrial respiratory chain) is sensitive to cyanide action (Way 1984). Due to its inhibition, oxygen cannot be utilized, histotoxic hypoxia develops, and this can lead to deaths of humans and animals (see Section 2.3.3). 

Fullerene showed antibacterial activity, which can be attributed to different interactions of C60 with biomolecules (Da Ros et al., 1996). In fact, there is a possibility to induce cell membrane disruption. The fullerene sphere seems not really adaptable to planar cellular surface, but for sure the hydrophobic surface can easily interact with membrane lipids and intercalate into them. However, it has been demonstrated that fullerene derivatives can inhibit bacterial growth by unpairing the respiratory chain. There is, first, a decrease of oxygen uptake at low fullerene derivative concentration, and then an increase of oxygen uptake, which is followed by an enhancement of hydrogen peroxide production. The higher concentration of C60 seems to produce an electron leak from the bacterial respiratory chain (Mashino et al., 2003). 

Mashino T, Usui N, Okuda K, Hirota T, Mochizuki M (2003) Respiratory chain inhibition by fullerene derivatives Hydrogen peroxide production caused by fullerene derivatives and a respiratory chain system. Bioorg. Med. Chem. 11 1433-1438. 

As the AO with a direct nonspecific mechanism of action we have chosen Hypoxene - sodium poly(2,5-dihydroxiphenyl)-4-thiosulfonate. Besides a direct AO effect as a scavenger of free radicals it exerts an anti-hypoxic effect shunting I and II complexes of mitochondrial respiratory chain, which are inhibited as a consequence of hypoxia (Eropkin et al., 2007). Hypoxene was introduced into cell incubation media before illumination and left during cells further incubation. Hypoxene in the concentration of 40pg/ml, comparable to doses applied in vivo, completely blocked C60-induced phototoxicity (Table 7.3). Cellular viability has completely recovered to control level, which is a convincing evidence of free radical nature of cellular damage in photodynamic effect of fullerene. 

In the absence of oxygen—i. e., in anaerobic conditions—the picture changes completely. Since O2 is missing as the electron acceptor for the respiratory chain, NADH+H and QH2 can no longer be reoxidized. Consequently, not only is mitochondrial ATP synthesis halted, but also almost the whole metabolism in the mitochondrial matrix. The main reason for this is the high NADH+H concentration and lack of NAD which inhibit the tricarbox-... 

The toxic potential of methyl mercaptan is due to its reversible inhibition of cytochrome c oxidase at the end of the respiratory chain of mitochondria. ... 

Owen, M.K, Doran, E. and Halestrap, A.P. (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. The Biochemical Journal, 348 (Pt. 3), 607-614. 

Primaquine is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mechanism by which 8-aminoquinolines exert their antimalarial effects is thought to be through a quinoline-quinone metabolite that inhibits the coenzyme Q-mediated respiratory chain of the exoerythrocytic parasite. 

The toxicity of fluoroacetic acid and of its derivatives has played an historical decisive role at the conceptual level. Indeed, it demonstrates that a fluorinated analogue of a natural substrate could have an activity profile that is far different from that of the nonfluorinated parent compound. The toxicity of fluoroacetic acid is due to its ability to block the citric acid cycle (Krebs cycle), which is an essential process of the respiratory chain. The fluoroacetate is transformed in vivo into 2-fluorocitrate by the citrate synthase. It is generally admitted that aconitase (the enzyme that performs the following step of the Krebs cycle) is inhibited by 2-fluorocitrate the formation of aconitate through elimination of the water molecule is a priori impossible from this substrate analogue (Figure 7.1). 

It is interesting that a new group of fungicides based on the natural products from the fungus Strobilurus tenacellus also inhibit mitochondrial respiration at the site of complex III (bei-complex) of the respiratory chain (see Chapter 4). Recently synthesised compounds from within this class are showing interesting insecticidal effects. 

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