Modulation of matrix Ca2+ content by the ADP/ATP carrier in brown adipose tissue mitochondria. Influence of membrane lipid composition

Chávez, Edmundo; Moreno‐Sánchez, Rafael; Torres-Márquez, M. Eugenia; Zazueta, Cecilia; Bravo, Concepciòn; Rodríquez-Enriquez, Sara; Garcı́a, Cruz; Rodríguez, José; Martı́nez, Federico

doi:10.1007/bf02109905

Cited by 8 publications

(6 citation statements)

References 45 publications

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“…Carboxyatractylate (CAT) (Figures 1, 4 and 5) and bongkrekate (BKA) (Figure 9), potent and highly specific inhibitors of ANT (Klingenberg, 1975), strongly inhibited uncoupling induced by hydroxynonenal in mitochondria from kidney, liver, heart and skeletal muscle. ANT is present in BAT mitochondria at about the same concentration as it is in liver mitochondria (Chavez et al ., 1996), and in BAT mitochondria (Figure 6) carboxyatractylate inhibited hydroxynonenal‐induced uncoupling by about the same absolute extent as it did in liver mitochondria (Figure 4A). However, because of the high UCP1 concentration in BAT mitochondria, the percentage inhibition by carboxyatractylate was much less than it was in mitochondria from the other tissues.…”

Section: Resultsmentioning

confidence: 99%

A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

et al. 2003

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Oxidative stress and mitochondrial dysfunction are associated with disease and aging. Oxidative stress results from overproduction of reactive oxygen species (ROS), often leading to peroxidation of membrane phospholipids and production of reactive aldehydes, particularly 4-hydroxy-2-nonenal. Mild uncoupling of oxidative phosphorylation protects by decreasing mitochondrial ROS production. We find that hydroxynonenal and structurally related compounds (such as trans-retinoic acid, trans-retinal and other 2-alkenals) specifically induce uncoupling of mitochondria through the uncoupling proteins UCP1, UCP2 and UCP3 and the adenine nucleotide translocase (ANT). Hydroxynonenal-induced uncoupling was inhibited by potent inhibitors of ANT (carboxyatractylate and bongkrekate) and UCP (GDP). The GDP-sensitive proton conductance induced by hydroxynonenal correlated with tissue expression of UCPs, appeared in yeast mitochondria expressing UCP1 and was absent in skeletal muscle mitochondria from UCP3 knockout mice. The carboxyatractylate-sensitive hydroxynonenal stimulation correlated with ANT content in mitochondria from Drosophila melanogaster expressing different amounts of ANT. Our findings indicate that hydroxynonenal is not merely toxic, but may be a biological signal to induce uncoupling through UCPs and ANT and thus decrease mitochondrial ROS production.

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Section: Resultsmentioning

confidence: 99%

A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

et al. 2003

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“…Cardiolipin may modulate apoptotic processes by inhibiting MPT. In fact, it provides an increased pool of negative ions that nonspecifically bind Ca 2+ , thereby preventing it from binding to protein sites that induce the opening of mitochondrial pores 45. Lieser et al46 found that mitochondrial cardiolipin content increased 10 days after BDL and thus protected against cell death by increasing the threshold for MPT.…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress

et al. 2004

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Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in primary biliary cirrhosis and prolongs survival free of liver transplantation. Recently, it was suggested that the cytoprotective mechanisms of UDCA may be mediated by protection against oxidative stress, which is involved in the development of cirrhosis induced by chronic cholestasis. The aims of the current study were 1) to identify the mechanisms involved in glutathione depletion, oxidative stress, and mitochondrial impairment during biliary cirrhosis induced by chronic cholestasis in rats; and 2) to determine the mechanisms associated with the protective effects of UDCA against secondary biliary cirrhosis. The findings of the current study indicate that UDCA partially prevents hepatic and mitochondrial glutathione depletion and oxidation resulting from chronic cholestasis. Impairment of biliary excretion was accompanied by decreased steady-state hepatic levels of ␥-glutamyl cysteine synthetase and ␥-cystathionase messenger RNAs. UDCA treatment led to up-regulation of ␥-glutamyl cysteine synthetase in animals with secondary biliary cirrhosis and prevented the marked increases in mitochondrial peroxide production and hydroxynonenalprotein adduct production that are observed during chronic cholestasis. A population of damaged and primarily apoptotic hepatocytes characterized by dramatic decreases in mitochondrial cardiolipin levels and membrane potential as well as phosphatidylserine exposure evolves in secondary biliary cirrhosis. UDCA treatment prevents the growth of this population along with the decreases in mitochondrial cardiolipin levels and membrane potential that are induced by chronic cholestasis. In conclusion, UDCA treatment enhances the antioxidant defense mediated by glutathione; in doing so, this treatment prevents cardiolipin depletion and cell injury in animals with secondary biliary cirrhosis. (HEPATOLOGY 2004;39:711-720.)

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“…These values correlated with a diminution in ANT levels, from 58 nmol/mg in control rats to 40 nmol/mg in hypothyroid rats. In addition to its normal function, ANT forms the inner membrane channel of the mitochondrial permeability transition pore (MPTP) [13–15] which allows the movement of matrix ions and metabolites through the mitochondrial membrane (Figure 1). Binding of cyclophilin-D (CyP-D) to ANT matrix surface facilitates a calcium-triggered conformational change converting it from a specific transporter to a nonspecific pore.…”

Section: Hypothyroidism and Mitochondriamentioning

confidence: 99%

“…Binding of cyclophilin-D (CyP-D) to ANT matrix surface facilitates a calcium-triggered conformational change converting it from a specific transporter to a nonspecific pore. Both proteins along with the voltage-dependent anion channel (VDAC) and cardiolipin probably represent the minimum MPTP configuration [13–15]. Once integrated, MPTP opening is favored by Ca 2+ accumulation in the matrix or by inhibiting the ADP/ATP translocase activity with the specific inhibitor carboxyatractyloside (CAT) [16].…”

Section: Hypothyroidism and Mitochondriamentioning

confidence: 99%

“…The resistance to increased permeability in mitochondria from hypothyroid rats should be due to the inability of ANT to convert itself into a nonspecific pore. Such a failure must be attributed to the low content of cardiolipin, which is part of the annulus of the carrier [12, 15] and is indispensable for its adequate function. Furthermore, it has been proposed that cardiolipin would be the target site for Ca 2+ to induce pore opening (Figure 1).…”

Section: Hypothyroidism and Mitochondriamentioning

confidence: 99%

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Pleiotropic Effects of Thyroid Hormones: Learning from Hypothyroidism

Franco

Chávez

Pérez-Méndez

2011

Journal of Thyroid Research

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Hypothyroidism induces several metabolic changes that allow understanding some physiopathological mechanisms. Under experimental hypothyroid conditions in rats, heart and kidney are protected against oxidative damage induced by ischemia reperfusion. An increased resistance to opening of the permeability transition pore seems to be at the basis of such protection. Moreover, glomerular filtration rate of hypothyroid kidney is low as a result of adenosine receptors-induced renal vasoconstriction. The vascular tone of aorta is also regulated by adenosine in hypothyroid conditions. In other context, thyroid hormones regulate lipoprotein metabolism. High plasma level of LDL cholesterol is a common feature in hypothyroidism, due to a low expression of the hepatic LDL receptor. In contrast, HDL-cholesterol plasma levels are variable in hypothyroidism; several proteins involved in HDL metabolism and structure are expressed at lower levels in experimental hypothyroidism. Based on the positive influence of thyroid hormones on lipoprotein metabolism, thyromimetic drugs are promising for the treatment of dyslipidemias. In summary, hypothyroid status has been useful to understand molecular mechanisms involved in ischemia reperfusion, regulation of vascular function and intravascular metabolism of lipoproteins.

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Modulation of matrix Ca2+ content by the ADP/ATP carrier in brown adipose tissue mitochondria. Influence of membrane lipid composition

Cited by 8 publications

References 45 publications

A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

A signalling role for 4-hydroxy-2-nonenal in regulation of mitochondrial uncoupling

Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress

Pleiotropic Effects of Thyroid Hormones: Learning from Hypothyroidism

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