Mitochondrial respiration, inhibition

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). 

B. Beltran, M. Quintero, E. Garcia-Zaragoza, E. O Connor, J.V. Esplugues, and S. Moncada, Inhibition of mitochondrial respiration by endogenous nitric oxide a critical step in Fas signaling. Proc. Natl. Acad. Sci. U.S.A. 99, 8892 (2002). 

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. 

Matsunaga FI, Saita T, Nagumo F, Mori M, Katano M. (1995). A possible mechanism for the cytotoxicity of a polyacetylenic alcohol, panaxytriol inhibition of mitochondrial respiration. Cancer Chemother Pharmacol. 35(4) 291-96. 

Formaldehyde treatment with low concentrations of formaldehyde can lead to a series of effects, one example being the decrease in mitochondrial membrane potential and the inhibition of mitochondrial respiration. 

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. 

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). 

C. Bronchoconstriction and secretion and muscular weaknesses occur from acetylcholine accumulation after inhibition of acetylcholinesterase. Parathion is an organophosphate insecticide that inhibits acetylcholinesterase, and it is readily available. Poisoning with compound 1080 (fluorocitrate) inhibits mitochondrial respiration and causes seizures and car-... 

Kay P., P.A. Blackwell, and A.B.A. Boxall (2004). Pate of veterinary antibiotics in a macro-porous tile drained clay soil. Environmental Toxicology and Chemistry 23 1136-1144. Keller B.J., H. Yamanaka, and R.G. Thurman (1992). Inhibition of mitochondrial respiration and oxygen-dependent hepatoxicity by six structurally dissimilar peroxisomal proliferating agents. Toxicology 71 49-61. 

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. 

The conjugate of hexachlorobutadiene inhibits mitochondrial respiration in vitro, and this may be the ultimate target in the kidney. Damage to DNA also occurs, and this could underlie some of the toxicity. 

The result of formate accumulation is metabolic acidosis. However, at later stages, the acidosis may also involve the accumulation of other anions such as lactate. This may be a result of inhibition of cytochrome oxidase and hence of mitochondrial respiration, tissue hypoxia due to reduced circulation of blood, or an increase in the NADH/NAD ratio. The acidosis that results from methanol poisoning will result in more formic acid being in the nonionized state and hence more readily able to enter the CNS. This will cause central depression and hypotension and increased lactate production. This situation is known as the "circulus hypoxicus."... 

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