Mitochondrial respiration, uncoupler

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). 

The major types of adipose tissue are (1) white adipose tissue, which manufactures, stores, and releases lipid and (2) brown adipose tissue, which dissipates energy via uncoupled mitochondrial respiration. Obesity research includes evaluation of the activity of adrenergic receptors and their effect on adipose tissue with respect to energy storage and expenditure or thermogenesis. 

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). 

Studies on the modes of action of dialkylpiperidines have shown that these compounds cause diverse biochemical lesions. These alkaloids which are powerful hemolysins (26) and dermal necrotoxins (27, 28), also release histamine from mast cells ( 9), thus functioning as effective algogens. In addition, these fire ant products inhibit Na+ and K+ ATPases 30) and at low concentrations uncouple oxidative phosphorylation leading to reduced mitochondrial respiration (31). 2,6-Disubstituted... 

Stockdale, M., Selwyn, M.J. (1971) Effects of ring substituents on the activity of phenols as inhibitors and uncouplers of mitochondrial respiration. Eur. J. Biochem. 21, 565-574. 

One logical consequence of the Na /Ca cycle, which is a futile cycle, is energy dissipation. Crompton et al. [88] have indeed demonstrated that Na, added to heart mitochondria after the accumulation of a pulse of Ca, uncouples respiration in a ruthenium red-sensitive way. The level of energy-dissipation due to the Na /Ca cycle in vivo, however, is most likely marginal, if one considers that the Ca uptake leg of the cycle, which determines the actual uncoupling of mitochondrial respiration, probably functions at a fraction of its maximal capability (see above). It has been mentioned already that the calculated rate of Ca recycling, admittedly in liver mitochondria where the Na -promoted release route is very poorly represented, corresponds to the re-uptake of only about 0.05 nmol Ca mg ... 

The mechanism of citrinin-induced nephrotoxicity has not been completely elucidated. However, it appears that citrinin accumulates in proximal tubular cells via the organic anion transporter, and that the parent compound is the nephrotoxicant species. Mitochondria are early targets for citrinin with multiple effects on mitochondrial function observed following exposure of mitochondria to citrinin, including uncoupling of mitochondrial respiration. The subsequent lost of cellular ATP content may eventually lead to cell death. 

PFOA is thought to induce peroxisome proliferation and interfere with mitochondrial metabolic pathways. Direct measurements revealed that PFOA uncouple mitochondrial respiration by increasing... 

Because of its very high toxicity to fish, it has been superseded by diphenyl ethers which have low toxicity to fish. Pentachlorophenol is an uncoupling agent and can prevent ATP formation in mitochondrial respiration. (Weinbach and Garbus, 1966). 

Fromenty B, Fisch C, Berson A, Letteron P, Larrey D, Pessayre D (1990b) Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II. J Pharmacol Exp Ther 255 1377-1384... 

By definition, the uncoupling effect of certain flavonoids should be independent of their inhibitory effects on mitochondrial respiration or FoFi-ATPase, suggesting an additional mode of action of flavonoids against mitochondrial function. A collapse of the transmembrane potential is likely under conditions in which the permeability barrier created by the mitochondrial inner membrane is compromised (as occurs in the presence of ionophores). Calcium, phosphate, oxidative stress, adenine nucleotide depletion, and membrane depolarization can induce such a nonspecific increase in the permeability of the inner membrane, in an event called the mitochondrial permeability transition (MPT) [30,34]. The MPT can be selectively inhibited by cyclosporin A and is believed to involve the assembly of a multiprotein complex to form a nonspecific pore that spans the inner and outer mitochondrial membranes. The latter assembly is referred to as the permeability transition pore complex (PTPC) (Fig. 1). Its exact composition is unknown, but appears to comprise cyclophilin D, ANT, the voltage-dependent anion channel (porin), and a benzodiazepinebinding site [10,30,34]. 

An ex vivo study with rat hepatocytes found a strong correlation between the cytotoxicity of a flavonoid and its ability to induce an early collapse of the mitochondrial transmembrane potential [6]. In contrast, nontoxic flavonoids had no effect on the transmembrane potential. As discussed previously, the ability of flavonoids and isoflavones to inhibit mitochondrial respiration and adenosine triphosphate (ATP) synthesis or uncouple oxidative phosphorylation represents a potential mechanism whereby they can trigger dissipation of the transmembrane potential and thus cytochrome c-dependent apoptosis. Thus, it is interesting to note that epicatechin, which had little or no proapoptotic effect in cancer cells [64] and exerted antiapoptotic effects in primary culture models [7,8,59], had essentially no inhibitory effect against complex I, II, or HI activity and FoFi-ATPase activity [24,25]. However, the preceding discussion has also indicated that the pro- or antiapoptotic effects of flavonoids may be explained by more specific mechanisms, potentially independently of their antioxidant capacity. These include effects on protein kinase cascades and gene expression, including MARK and the Bcl-2 family of proteins. 

Many inhibitors of substrate oxidations, substrate transport, electron transport, and ATP synthesis are known including many well-known toxins (see Sherratt, 1981 Harold, 1986 Nicholls and Ferguson, 1992). These are not discussed here except to mention specific uncouplers of oxidative phosphorylation. Classic uncouplers such as 2,4-dinitrophenol have protonated and unprotonated forms, both of which are lipid soluble and cross the inner mitochondrial membrane discharging the proton gradient. This prevents ATP synthesis and stimulates respiration. 

---