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Am J Physiol Endocrinol Metab 293: E1320-E1324, 2007. First published August 14, 2007; doi:10.1152/ajpendo.00138.2007
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Adenine nucleotide translocator promotes oxidative phosphorylation and mild uncoupling in mitochondria after dexamethasone treatment

Matthieu Arvier,1 Laëtitia Lagoutte,1 Gyasi Johnson,1 Jean-François Dumas,1 Benoit Sion,2 Genevieve Grizard,2 Yves Malthièry,1 Gilles Simard,1 and Patrick Ritz1

1Institut National de la Santé et de la Recherche Médicale, Unité 694, Laboratoire de Biochimie et de Biologie Moléculaire, Centre Hospitalier Universitaire, Angers, France; and 2Université de Clermont-Ferrand EA 975, Clermont-Ferrand, France

Submitted 1 March 2007 ; accepted in final form 1 August 2007


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
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 DISCUSSION
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The composition of the mitochondrial inner membrane and uncoupling protein [such as adenine nucleotide translocator (ANT)] contents are the main factors involved in the energy-wasting proton leak. This leak is increased by glucocorticoid treatment under nonphosphorylating conditions. The aim of this study was to investigate mechanisms involved in glucocorticoid-induced proton leak and to evaluate the consequences in more physiological conditions (between states 4 and 3). Isolated liver mitochondria, obtained from dexamethasone-treated rats (1.5 mg·kg–1·day–1), were studied by polarography, Western blotting, and high-performance thin-layer chromatography. We confirmed that dexamethasone treatment in rats induces a proton leak in state 4 that is associated with an increased ANT content, although without any change in membrane surface or lipid composition. Between states 4 and 3, dexamethasone stimulates ATP synthesis by increasing both the mitochondrial ANT and F1-F0 ATP synthase content. In conclusion, dexamethasone increases mitochondrial capacity to generate ATP by modifying ANT and ATP synthase. The side effect is an increased leak in nonphosphorylating conditions.

ATP production efficiency; glucocorticoids; mitochondrial proton leak

GLUCOCORTICOID HORMONES ARE known to regulate various biological functions such as carbohydrate, protein, and fat metabolism (28). Glucocorticoid treatment, particularly with dexamethasone, induces a hypercatabolic state characterized by accelerated protein turnover in skeletal muscle and gluconeogenesis in the liver, leading finally to augmented energy expenditure. Indeed, dexamethasone administration in healthy humans is associated with an increase in the resting energy expenditure (5, 16, 22, 29), which corresponds to a higher oxygen consumption at the whole body level. We have suggested that the increased energy expenditure may be linked to the effect of glucocorticoids on mitochondria (8, 27, 28). Because 20% of the resting metabolism is due to futile proton cycles across the inner mitochondrial membrane (26), we focused on the proton leak, and our group recently reported that dexamethasone treatment increases nonphosphorylating respiration (8) and basal proton conductance (27) in rat liver mitochondria. Roussel and colleagues (8, 27) have estimated that these phenomena explain a 3% increase in whole-body oxygen consumption.

The exact mechanism of basal proton conductance in mitochondria is not completely understood. Many studies have reported consistent correlations between proton conductance and the inner membrane surface area or the phospholipid composition in mitochondria from different tissues and different species (7, 12, 23). A close relationship has also been established between the basal proton leak and the adenine nucleotide translocator (ANT) content (3). Taking these findings into account, we were led to hypothesize that dexamethasone promotes the proton leak by increasing the mitochondrial ANT content.

In nonphysiological conditions, such as saturating ADP concentrations, dexamethasone is known to lower the ATP-to-oxygen atom ratio (ATP/O) (15, 17, 19) and may reduce the efficiency of mitochondrial oxidative phosphorylation (28). However, mitochondria usually work between state 4 and state 3, conditions that have never been investigated in previous studies. This can be assessed by generating different steady states of ADP concentrations with hexokinase titration. By using such an approach, we conclude that, in this more physiological state, mitochondria from dexamethasone-treated rats exhibit a higher capacity for ATP production. This is probably achieved by an increase in both ANT and ATP synthase content.


   MATERIALS AND METHODS
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RESULTS
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Reagents and standards. Chemicals and reagents were purchased from Sigma Aldrich (Saint Quentin Fallavier, France) except for Tris and Tris·HCl, which were obtained from Eurobio (Les Ulis, France). Triphenylmethylphosphonium and methanol were purchased from Merck (VWR International, Strasbourg, France), BSA and NADH were from Roche-Boehringer (Meylan, France), bicinchoninic acid assay kit and phospholipids standards were from Interchim (Montluçon, France), and chloroform and hexane were from Prolabo (Fontenay-sous-Bois, France).

Animals. All investigations were performed according to the guidelines for the care and use of animals from the French Department of Animal and Environmental Protection. These investigations were conducted in a facility approved by The Direction des Services Vétérinaires, by investigators approved by the DSV. Sixteen male Sprague-Dawley rats, born and bred in our animal facilities, were housed in individual cages from the age of 13 wk (330–400 g). Animals were provided with water ad libitum and a standard diet (U-A-R A04) composed of (% total weight) 16% protein, 3% fat, 60% carbohydrate, and 21% water, fiber, vitamins, and minerals. The metabolizable energy content was 2.9 kcal/day. Rats were randomly allocated into two groups (8 rats per group) as follows: the control group and the dexamethasone-treated group. Dexamethasone-treated rats received a daily intraperitoneal injection of 1.5 mg/kg of dexamethasone for 5 days. All rats were fasted during the night following the 5th day. On the 6th day, animals were killed by decapitation.

Preparation of liver mitochondria. Liver mitochondria were prepared as previously described (21) in a medium containing (in mM) 100 sucrose, 50 KCl, 5 EGTA, and 50 Tris·HCl (pH 7.4). Protein concentrations were determined by the bicinchoninic acid assay kit (Interchim) with BSA used as a standard.

Mitochondrial respiration, membrane potential, and ATP synthesis. Oxygen consumption and membrane potential were measured simultaneously in a closed, stirred Perspex chamber fitted with a Clark oxygen electrode (Rank Brothers, Cambridge, UK) and an electrode sensitive to the potential-dependent probe triphenylmethylphosphonium (TPMP). Mitochondria (0.5 mg protein/ml) were incubated in a respiratory reaction medium consisting of 120 mM KCl, 5 mM KH2PO4, 1 mM EGTA, 2 mM MgCl2, 5 µM rotenone, 80 ng/ml nigericin, and 3 mM HEPES (pH 7.4, 30°C) supplemented with 0.3% (wt/vol) BSA and saturated with room air. The TPMP electrode was calibrated by sequential 0.5 µM additions up to 2 µM TPMP, after which 5 mM succinate was added to start the reaction. After each run, 2 µM FCCP was added to dissipate the membrane potential and release all of the TPMP back into the medium for baseline correction, if needed. Membrane potentials were calculated as previously described (25), assuming a TPMP binding correction of 0.42·µl–1·mg of protein–1 for liver mitochondria (26).

The proton leak kinetics was established by carrying out titrations with nonphosphorylating mitochondria. The respiration and the inner membrane potential were progressively inhibited through successive steady states induced by the addition of malonate (up to 5 mM) in the presence of oligomycin (3 µg/ml).

In phosphorylating mitochondria, the kinetic response of substrate oxidation and the ATP/O were measured in the respiratory reaction medium supplemented with 20 mM glucose and 125 µM ATP, with increasing concentrations of hexokinase ranging from 0.01 to 0.225 U/ml, in the absence of oligomycin.

Mitochondrial enzyme activities. The activity of citrate synthase was measured in a reaction medium consisting of 100 mM Tris·HCl, 40 µg/ml 5,5'-dithio-bis(2-nitrobenzoic acid), 1 mM oxaloacetate, 0.3 mM acetyl CoA, and 4% Triton X-100 (pH 8.1). After 3 min of incubation, the reaction was initiated by adding the homogenate (20–50 µg protein), and the change in optical density at 412 nm was recorded for 3 min.

Fractionation of mitochondria with the use of Percoll gradients. For lipid analysis and to avoid contamination with broken plasma membrane or endoplasmic reticulum, a portion of the isolated mitochondria was further fractionated on a discontinuous Percoll gradient (60, 30, and 18% Percoll). Mitochondria were charged on the top of the gradient and centrifuged at 8,700 g for 1 h. After centrifugation, mitochondria were collected at the 30–60% interface and washed two times with an isolation buffer (10,000 g for 10 min). The pellet was dissolved in a small volume of the isolation buffer and stored at –80°C. Whole mitochondria from the Percoll gradient isolations were used to determine the mitochondrial phospholipid and fatty acid composition.

Preparation of samples for lipid analysis. Lipids were extracted by the method of Folch et al. (10). Briefly, 5 mg of mitochondrial protein were extracted with a mixture of CHCl3-MeOH (1:2 vol/vol) containing 0.005% butylated hydroxyl-toluene to avoid the peroxidation of polyunsaturated fatty acids. After vortex mixing, 1 ml of water was added to the mixture, which was again vortex mixed and allowed to stand at room temperature for 1 h before centrifugation at 500 g for 10 min. The organic layer was then collected, and the pellet was reextracted. All of the organic layers were pooled and dried in a solvent evaporator. The dry material was dissolved in 500 µl of CHCl3-MeOH (2:1, vol/vol) and stored at –80°C awaiting analysis.

Identification of phospholipids by high-performance thin-layer chromatography. High-performance thin-layer chromatography plates were used after prewashing with a mixture of chloroform-methanol (1:1, vol/vol), followed by heating at 130°C for 1 h. The plates were developed with hexane-diethyl ether-glacial acetic acid (80:20:2, vol/vol) or with chloroform-acetone-methanol-acetic acid-water (7:8:1:2:1, vol/vol). The plates were then sprayed with 10% (wt/vol) copper sulfate in 8% (vol/vol) phosphoric acid solution and heated at 160°C for 15 min to stain all of the phospholipids, which were finally identified by reference to standards.

Western blotting. Equal amounts of mitochondrial proteins (15 µg) from each sample (control and dexamethasone-treated rats, n = 8) were boiled in the loading buffer and resolved by 12.5% SDS polyacrylamide gels. For immunoblotting, proteins were transferred onto a polyvinylidene difluoride membrane (Hybond-P; Amersham Biosciences) with Tris-glycine electroblotting buffer for 1 h at 260 mA. The blot was blocked for 3 h in a blocking reagent [3% BSA (wt/vol) in 1x PBS], washed two times in 1x Tris-buffered saline-Tween 20 for 10 min, and probed overnight at room temperature with a monoclonal antibody, anti-ANT and anti-HSP60 (1:1,000 and 1:1,000 dilution; Calbiochem and Stressgen Reagent), or with anti-porin and anti-ATP synthase beta-subunit antibodies (1:2,500 and 1:500 dilution; Calbiochem and Molecular Probes). The blot was washed three times for 10 min in 1x Tris-buffered saline-Tween 20 and probed for 1 h at room temperature with peroxidase-conjugated rabbit anti-mouse IgG (1:20,000; Interchim). Signals were visualized on high-performance chemiluminescence film (Kodak X-Omat) using an enhanced chemiluminescence procedure (Amersham France, Les Ulis, France). The membranes were scanned with the GS-800 calibrated imaging densitometer (Bio-Rad, Hercules, CA), and the signals were analyzed with Quantity One software (Bio-Rad).

Statistical analysis. All results are expressed as mean values ± SE. All comparisons between dexamethasone-treated rats and controls were made with the Mann-Whitney test. A value of P ≤0.05 was considered significant in all cases. The statistical analyses were performed with SPSS for Windows, version 13.0 (SPSS, Chicago, IL).


   RESULTS
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Mitochondrial membrane potential and oxygen consumption in state 4 respiration. Figure 1 shows the relationship between oxygen consumption and the mitochondrial membrane potential in the nonphosphorylating condition. The generation of a given membrane potential required greater oxygen consumption in dexamethasone-treated rats than in controls. Thus, for a membrane potential of 190 mV, the oxygen consumption was significantly higher in dexamethasone-treated than in control rats (23.4 ± 7.4 vs. 17.8 ± 2.8 nanoatoms O·min–1·mg protein–1; P < 0.05).


Figure 1
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  		Fig. 1. Relationship between the oxygen consumption rate and the mitochondrial membrane potential in the presence of oligomycin. {blacksquare}, Control (CON) rats; {square}, dexamethasone-treated (DEXA) rats. Results are mean values ± SE; n = 8 rats.

 
Mitochondrial membrane potential and oxygen consumption between state 4 and state 3 of respiration. The relationship between the mitochondrial membrane potential and oxygen consumption was linear for dexamethasone-treated and for control rats (Fig. 2); the mitochondrial membrane potentials were significantly lower in dexamethasone-treated than in control rats.


Figure 2
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  		Fig. 2. Relationship between the oxygen consumption rate and the mitochondrial membrane potential. The respiration rate was modulated by subsaturing ADP concentrations generated by hexokinase (0.01–0.225). {blacksquare}, CON rats; {square}, DEXA rats. Results are mean values ± SE; n = 8 rats.

 
Relationship between ATP synthesis and oxygen consumption between state 4 and state 3 of the respiration. The relationship between ATP synthesis and oxygen consumption stimulated by increasing hexokinase concentrations is summarized in Table 1. Without any addition of hexokinase (i.e., state 4), oxygen consumption was significantly higher for dexamethasone-treated rats than for control rats (P < 0.05). At maximal oxygen consumption (i.e., close to state 3, corresponding to ~90% of the classical state 3), ATP synthesis was significantly higher in dexamethasone-treated rats than in control rats (P < 0.05). There was a slight increase (but not significant) in oxygen consumption and ATP synthesis in dexamethasone-treated rats for the other values of hexokinase concentration. However, no differences in ATP/O were observed between dexamethasone-treated and control rats at any hexokinase addition value.


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  		Table 1. Oxygen consumption, ATP synthesis, and ATP/O in DEXA-treated rats, at different concentrations of hexokinase, vs. control rats

 
Mitochondrial citrate synthase activity. There was no difference in citrate synthase activity between dexamethasone-treated and control rats (294.4 ± 45.1 vs. 323.0 ± 85.4 nmol·min–1·mg of protein–1).

Mitochondrial phospholipid composition. Our results show that neither the mitochondrial phospholipid content nor the phospholipid composition was modified by dexamethasone treatment (Table 2). The total amount of phospholipid (expressed as mg of mitochondrial protein) was also unaffected by the treatment (0.146 ± 0.054 vs. 0.128 ± 0.024 mg of total phospholipids/mg of protein for dexamethasone-treated and control rats, respectively). This suggests a similarity of the mitochondrial membrane surface area in dexamethasone-treated and control rats.


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  		Table 2. Phospholipid content of the mitochondrial membrane in dexamethasone-treated vs. control rats

 
Analysis of the ATP synthase beta-subunit and ANT content by Western blotting. The relative content of the ATP synthase beta-subunit protein (Fig. 3) was significantly higher in dexamethasone-treated than in control rats (0.86 ± 0.04 vs. 0.60 ± 0.05; P < 0.05). The absolute mitochondrial ANT content (Fig. 4) was also significantly higher in dexamethasone-treated than in control rats (0.22 ± 0.02 vs. 0.09 ± 0.01; P < 0.001).


Figure 3
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  		Fig. 3. Western blot. Total proteins were transferred from polyacrylamide gels to a polyvinylidene difluoride membrane with Tris-glycine electroblotting buffer. The blot was probed overnight at room temperature with anti-porin and anti-ATP synthase beta-subunit. VDAC, voltage-dependent anion channel. The blot was then probed with peroxidase-conjugated rabbit anti-mouse IgG. Signals were visualized on high-performance chemiluminescence film using the enhanced chemiluminescence procedure. *P < 0.01.

 

Figure 4
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  		Fig. 4. Western blot. Total proteins were transferred from polyacrylamide gels to a PVDF membrane with Tris-glycine electroblotting buffer. The blot was probed overnight at room temperature with anti-porin and anti-adenine nucleotide translocator (ANT) antibodies. The blot was then probed with peroxidase-conjugated rabbit anti-mouse IgG. Signals were visualized on high-performance chemiluminescence film using the enhanced chemiluminescence procedure. *P < 0.01.

 

   DISCUSSION
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 MATERIALS AND METHODS
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This study gives evidence for a direct impact of glucocorticoids on the efficiency of oxidative phosphorylation. We have previously shown that dexamethasone treatment in rats increased the proton leak (27). In the present study, we confirm this result and show that, in more physiological conditions, i.e., between state 4 and state 3, the ATP synthesis was significantly higher in dexamethasone-treated than in control rats. We also found that the ANT and the ATP synthase beta-subunit contents were significantly increased by the dexamethasone treatment.

We recently reported that the basal proton conductance of the mitochondrial inner membrane is very different in liver mitochondria of rats given glucocorticoids (8, 27). Among the factors known to affect proton conductance, there is the phospholipid composition of the membrane (2, 4, 13). Many correlative studies comparing mitochondria from different tissues in different species with various thyroid hormonal states have demonstrated the importance of the mitochondrial inner membrane surface area and the phospholipid composition as determinants of the basal proton leak (6, 7). In our study, the evaluation of these factors was performed on whole mitochondria isolated on Percoll gradients, assuming that, at least in the rat liver, the phospholipid content of whole mitochondria reflects the composition of the inner membrane. Our results clearly indicate that dexamethasone treatment modifies neither the membrane surface area nor the phospholipid composition of mitochondria. Natural differences in basal proton conductance also correlate with differences in the fatty acyl composition of phospholipids, and dexamethasone has been reported to depress delta-6- and delta-5-desaturase while increasing delta-9-desaturase in the liver. However, it is unlikely that the increased proton leak that we observed in dexamethasone-treated rats was the result of modification of the fatty acid composition. The proton permeability of liposomes made from mitochondrial inner membrane phospholipids is almost unaffected by the phospholipid fatty acid composition, and the main effects of dexamethasone, i.e., the increase in oleic acid and the decrease in arachidonic acid, are generally associated with low proton conductance. Nevertheless, we cannot totally exclude the possibility that dexamethasone treatment may specifically modify the acyl composition of some classes of phospholipids. This point needs to be addressed in further studies.

Brand et al. (3) recently stated that there is a striking correlation between mitochondrial proton leak and ANT content of the mitochondrial inner membrane and suggested that ANT is a major catalyst of the basal fatty-acid-independent proton leak in mitochondria. We found that the dexamethasone treatment increased the ANT content; in fact, dexamethasone-treated rats showed a 100% increase in the ANT content compared with controls. This indicates that the increased ANT content is a major factor in increasing the mitochondrial proton leak in dexamethasone-treated rats. The shift to the left of the nonohmic part of the Nichol's curve confirms that mitochondria from dexamethasone-treated rats display an increase in proton leak. This accounts for the increase in state 4 respiratory rates together with the decrease in protonmotive force that we previously reported (8, 27). However, the ohmic part of the curve is clearly not affected. This led us to exclude a single protonophoric effect of the increased ANT content (24). Moreover, as discussed below, the greater ANT content does not deteriorate the efficiency of such mitochondria since control and dexamethasone-treated rats exhibit similar ATP/O, whereas the protonmotive forces are quite different (see Fig. 2). This clearly indicates that, in phosphorylating conditions, the energy wastage (proton leak and/or redox slip) is comparable in dexamethasone-treated rats and in control rats.

Many studies (15, 17, 20) showed that dexamethasone administration lowers ATP/O. In our present study, we found no significant differences in ATP/O between control and dexamethasone-treated rats. This discrepancy is explained by the fact that ATP/O was not assessed the same way. In the previous studies, ATP/O ratios were only measured using a saturating concentration of ADP. In our present study, ATP/O was measured with a nonsaturating ADP-generating system based on hexokinase, which is more physiological. This means that we can be trustful on the fact that the ATP/O results are not significantly different between dexamethasone-treated and control rats under physiological respiratory state (between state 4 and state 3). Furthermore, ATP/O results are different between these two rat groups for higher oxygen consumption with the ADP saturating method (15, 17, 20, 28).

Because the ANT translocates ADP in the mitochondrial matrix, the higher ANT content is likely to increase the ADP flux, thereby enhancing the rate of oxidative phosphorylation (18). More ADP substrate will then be available for F1-FO ATP synthase. Furthermore, a decreased ATP-to-ADP concentration ratio stimulates oxygen consumption under phosphorylating conditions (14). F1-FO ATP synthase beta-subunit, i.e., the catalytic subunit, is increased and directly linked to the efficiency of mitochondrial ATP synthesis (12, 13). These results show that dexamethasone improves ATP synthesis in rat mitochondria (Fig. 4 and Table 1). Together, these results indicate that dexamethasone treatment increases the capacity of rat liver mitochondria to phosphorylate ATP.

Glucocorticoid treatment increases gluconeogenesis, lipolysis, and proteolysis (1, 5, 9, 16, 30). These pathways are large-scale consumers of ATP. Our results suggest that the mitochondrial response to ATP requirements is an increase in both the ADP input capacity and of ATP output capacity mediated by ANT. However, the higher ANT content may have a side effect: the increase in the basal proton leak under state 4 of respiration.

Proton leak explains 20% of the whole-body oxygen consumption (25). An increase in proton leak probably increases oxygen consumption (estimated to 3%) at the whole-body level (27). Between state 4 and state 3, mitochondrial oxygen consumption is mildly increased to support higher ATP synthesis. Together, because mitochondria contribute to 90% of the whole-body oxygen consumption, dexamethasone induced changes in mitochondrial metabolism that participate in the increase in resting energy expenditure.

In conclusion, the present study shows that, under physiological conditions, mitochondria of dexamethasone-treated rats improve their ATP production efficiency. Increased ANT and ATP synthase membrane contents may participate in this improvement, the side effect being an increased proton leak under state 4.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
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REFERENCES
 
This work was supported by grants from Contrat de Plan Etat Region 2000–2004.


   ACKNOWLEDGMENTS
 
The authors thank Pierre Legras, Jérôme Roux, and Dominique Gilbert for animal care and Kanaya Malkani for reviewing the English manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. Ritz, Medicine B, CHU, F-49033 Angers Cedex 01, France (e-mail: patrick.ritz{at}wanadoo.fr)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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