Search

There has been renewed interest in using mitochondrial uncoupler compounds such as niclosamide and carbonyl cyanide p‐(trifluoromethoxy)phenylhydrazone (FCCP) for the treatment of obesity, hepatosteatosis and diseases where oxidative stress plays a role. However, both FCCP and niclosamide have undesirable effects that are not due to mitochondrial uncoupling, such as inhibition of mitochondrial oxygen consumption by FCCP and induction of DNA damage by niclosamide. Through structure–activity analysis, we identified FCCP analogues that do not inhibit mitochondrial oxygen consumption but still provided good, although less potent, uncoupling activity. We also characterized the functional role of the niclosamide 4′‐nitro group, the phenolic hydroxy group and the anilide amino group in mediating uncoupling activity. Our structural investigations provide important information that will aid further drug development. [ABSTRACT FROM AUTHOR]

Mitochondrial permeability transition, due to opening of the permeability transition pore (PTP), is triggered by [Ca.sup.2+] in conjunction with an inducing agent such as phosphate. However, incubation of rat liver mitochondria in the presence of low micromolar concentrations of [Ca.sup.2+] and millimolar concentrations of phosphate is known to also cause net efflux of matrix adenine nucleotides via the ATP-Mg/[P.sub.i] carrier. This raises the possibility that adenine nucleotide depletion through this mechanism contributes to mitochondrial permeability transition. Results of this study show that phosphate-induced opening of the mitochondrial PTP is, at least in part, secondary to depletion of the intramitochondrial adenine nucleotide content via the ATP-Mg/[P.sub.i] carrier. Delaying net adenine nucleotide efflux from mitochondria also delays the onset of phosphate-induced PTP opening. Moreover, mitochondria that are depleted of matrix adenine nucleotides via the ATP-Mg/[P.sub.i] carrier show highly increased susceptibility to swelling induced by high [Ca.sub.2+] concentration, atractyloside, and the prooxidant tert-butylhydroperoxide. Thus the ATP-Mg/[P.sub.i] carrier, by regulating the matrix adenine nucleotide content, can modulate the sensitivity of rat liver mitochondria to undergo permeability transition. This has important implications for hepatocytes under cellular conditions in which the intramitochondrial adenine nucleotide pool size is depleted, such as in hypoxia or ischemia, or during reperfusion when the mitochondria are exposed to increased oxidative stress. adenine nucleotides; calcium; phosphate; hypoxia; transport

Research has been conducted on the beta cell sense glucose which stimulates insulin secretion. The role of the uncoupling protein-2 in regulating insulin secretion has been investigated and the results are reported.

Research has been conducted on the uncoupling proteins. Results indicate the difference between these proteins in their regulation by purine nucleotides and fatty acids.

Abstract The transcription factor Hypoxia-Inducible Factor-1α is a master regulator of the cellular response to low oxygen concentration. Compound C, an inhibitor of AMP-activated kinase, has been reported to inhibit hypoxia dependent Hypoxia-Inducible Factor-1α activation via a mechanism that is independent of AMP-activated kinase but dependent on its interaction with the mitochondrial electron transport chain. The objective of this study is to characterize the interaction of Compound C with the mitochondrial electron transport chain and to determine the mechanism through which the drug influences the stability of the Hypoxia-Inducible Factor-1α protein. We found that Compound C functions as an inhibitor of complex I of the mitochondrial electron transport chain as demonstrated by its effect on mitochondrial respiration. It also prevents hypoxia-induced Hypoxia-Inducible Factor-1α stabilization in a dose dependent manner. In addition, Compound C does not have significant effects on reactive oxygen species production from complex I via both forward and reverse electron flux. This study provides evidence that similar to other mitochondrial electron transport chain inhibitors, Compound C regulates Hypoxia-Inducible Factor-1α stability by controlling the cellular oxygen concentration.

Classic Galactosaemia is a genetic disorder, characterised by galactose intolerance in newborns. It occurs due to recessive mutations in the galactose‐1‐phosphate uridylyltransferase (GALT) gene. One of the main alterations caused by GALT deficiency is the accumulation of galactose 1‐phosphate (Gal‐1P) in cells. Studies have suggested that Gal‐1P exerts cellular toxicity, possibly by inhibiting cellular metabolism. However, the exact significance of Gal‐1P in disease pathogenesis remains unclear. In this study, we tested the hypothesis that Gal‐1P inhibits cellular glucose utilisation by competing with substrates in the glycolytic pathway. We also investigated the metabolism of both galactose and glucose in GALT‐expressing HEK293T and 143B cells to identify critical reactions steps contributing to the metabolic toxicity of galactose. Notably, we found that galactose‐treated HEK293T and 143B cells, which express endogenous GALT, accumulate markedly high intracellular Gal‐1P concentrations. Despite very high intracellular Gal‐1P concentrations, no inhibition of cellular glucose uptake and no significant changes in the intracellular concentrations of glycolytic metabolites were observed. This indicates that Gal‐1P does not exert an inhibitory effect on glycolysis in cells and rules out one potential hypothesis for cellular Gal‐1P toxicity. We also investigated the mechanism responsible for the observed Gal‐1P accumulation. Our results suggest that Gal‐1P accumulation is a result of both low GALT activity and the absence of product inhibition by Gal‐1P on galactokinase (GALK1), the enzyme responsible for phosphorylating galactose to Gal‐1P. These findings provide a better understanding of the disease mechanisms underlying Classic Galactoaemia. [ABSTRACT FROM AUTHOR]