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Article |
Correspondence to James D. Lechleiter: lechleiter{at}uthscsa.edu
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Abstract |
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L.M. John's current address is: Pfizer, Inc., CVMD Biology, Groton, CT 06340.
Abbreviations used in this paper: ANT, adenine nucleotide translocator; DBD, DNA binding domain;
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Introduction |
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Increasing evidence suggests that thyroid hormone exerts nontranscriptional effects on mitochondrial metabolism. Initial studies demonstrated that treatment of cells with 3,5,3'-tri-iodothyronine (T3) results in a rapid increase in O2 consumption and ATP production in rat liver mitochondria (Sterling, 1980). These effects persisted in the presence of protein synthesis inhibitors, suggesting that the mechanism of action was nontranscriptional. Sterling and coworkers (Sterling, 1980; Sterling and Brenner, 1995) additionally demonstrated that exposure of mitochondria to T3, isolated from rat hepatocytes, increased both ATP production and O2 consumption. Acute exposure of isolated mitochondria to thyroid hormone has also been reported to increase pH and to increase mitochondrial Ca2+ efflux (Sterling et al., 1980; Crespo-Armas and Mowbray, 1987; Soboll, 1993a). Mitochondrial localization of TRs was originally reported by Sterling and coworkers (Sterling, 1991). Later, Ardail et al. (1993) identified two high affinity T3 binding proteins in rat liver mitochondria. Wrutniak et al. (1995) and Casas et al. (1999) reported the presence of a high affinity (
43 kD) T3 binding protein in rat liver mitochondrial matrix extracts, which was identified as an NH2 terminus shortened form of rat TR
1 (rTR
F1). The full-length form of the rat thyroid hormone receptor alpha subtype 1 (rTR
1) is predominantly localized to the nucleus where it binds to DNA response elements and regulates transcriptional events (Wrutniak et al., 1995). Wrutniak (Wrutniak et al., 1995) suggested that the mitochondrial form of the rTR may be involved in mitochondrial transcriptional activity.
Intracellular Ca2+ signaling has been intimately linked to mitochondrial metabolism. Several dehydrogenases within the citric acid cycle are Ca2+ dependent (McCormack and Denton, 1989). Ca2+ uptake into the mitochondria is a passive process driven by the mitochondrial and occurs via the Ca2+ uniporter. Because of the low Ca2+ affinity of the uniporter, high cytosolic Ca2+ concentrations are required to cause significant mitochondrial Ca2+ uptake. Under physiological conditions, these concentrations only occur near an open ion channel pore. Consequently, close physical proximity between the ER and mitochondria is required for significant mitochondrial Ca2+ uptake (Rizzuto et al., 1998, 1999). Work from our laboratory also demonstrated that mitochondrial Ca2+ uptake itself modulated inositol 1,4,5-trisphosphate (IP3)-Ca2+ release (Jouaville et al., 1995). Subsequently, Hajnoczky et al. (1995) demonstrated that IP3-mediated Ca2+ oscillations efficiently stimulated mitochondrial metabolism. The local Ca2+ signaling between the ER and mitochondria has now been supported by many other investigators (Simpson and Russell, 1996; Hajnoczky et al., 1999; Szalai et al., 2000). Control of mitochondrial metabolism by matrix Ca2+ appears to be a fundamental mechanism whereby cells meet their energy requirements.
Xenopus laevis oocytes do not express detectable levels of endogenous TRs (Banker et al., 1991; Kawahara et al., 1991; Eliceiri and Brown, 1994). Induction of TR expression in Xenopus laevis occurs during the embryonic stages of development (Yaoita and Brown, 1990; Banker et al., 1991; Kawahara et al., 1991; Eliceiri and Brown, 1994). Consequently, Xenopus oocytes offer a unique model system to study the effects of thyroid hormones and their receptors on intracellular Ca2+ signaling and mitochondrial metabolism.
We present evidence demonstrating that thyroid hormone-activated TRs acutely regulate mitochondrial metabolism and, thereby, Ca2+ wave activity. Only expression of the NH2 terminustruncated forms of TR that target the mitochondria were effective at stimulating mitochondria. Transcriptionally inactive TRs were fully capable of modulating Ca2+ wave activity. These observations suggest an acute nontranscriptional pathway for modulation of intracellular Ca2+ signaling via thyroid hormone receptor-stimulated mitochondrial metabolism.
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Results |
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Subsequently, we tested whether the transcriptionally inactive xTRßA1 mutants could still acutely regulate Ca2+ signaling. Oocytes were injected with xTRßA1 mRNA or its mutants and protein expression levels were confirmed using Western analysis 23 d after injection (Fig. 4 c). Oocytes expressing xTRßA1 or the mutants were exposed to T3 (100 nM) 10 min before injection with IP3 (300 nM). Ca2+ activity was confocally imaged, as described above. The average Ca2+ interwave period for the control group (water-injected oocytes) was 6.6 ± 0.20 s (n = 70), which was significantly shorter than that in the xTRßA1 expressing oocytes (8.40 ± 0.30 s, n = 40; ANOVA single factor, P < 0.0001; Fig. 4 b, d; Fig. 1. More importantly, regulation of the Ca2+ wave period in oocytes expressing either the single mutant xTRßA1-
NLS (9.6 ± 0.48 s, n = 24) or the double mutant, xTRßA1
pBox-NLS (8.4 ± 0.28 s; n = 24) was indistinguishable from oocytes expressing wild-type xTRßA1 (Fig. 4, b and d). We conclude from these data that neither the pBOX nor the NLS of TRßA1 is required for acute regulation of Ca2+ signaling.
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Discussion |
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Application of thyroid hormones to mitochondria has long been known to increase metabolism (Sterling, 1980). Mitochondria were also known to be target organelles of T3 accumulation in cells (Sterling et al., 1984; Morel et al., 1996). However, a mitochondrial hormone receptor that mediated these effects has never been conclusively identified. Sterling (1986)(1991) initially suggested that the adenine nucleotide translocator (ANT) bound to T3 with high affinity. Romani et al. (1996) also suggested that thyroid hormone had its specific mitochondrial target site at the matrix side of ANT. They found that bongkrekic acid, a membrane-permeant inhibitor of ANT, blocked a thyroid hormone-induced release of Mg2+ from mitochondria. On the other hand, Wrutniak and coworkers (Wrutniak-Cabello et al., 2001) found no evidence demonstrating a direct interaction between ANT and T3. Our data indicate that ANT alone is not the thyroid hormone receptor that mediates the regulation of mitochondrial metabolism. Rather, our data reveal that a mitochondrial targeted TR is a required element of acute thyroid hormone regulation of metabolism. The use of Xenopus oocytes in these experiments was crucial in this determination because oocytes do not express endogenous TRs (Yaoita and Brown, 1990; Kawahara et al., 1991). The ubiquitous expression of endogenous TRs would have hidden this finding in earlier studies.
The ability of specific thyroid hormone receptors to target mitochondria has been demonstrated by other investigators. A truncated form of rat TR1 (rTR
1
F) and not its full-length form, localized to the matrix of mitochondria (Ardail et al., 1993; Wrutniak et al., 1995; Casas et al., 1999). Our work corroborated these reports and further demonstrated that the xTRßA1, which is highly similar to rTR
1
F, targeted the mitochondria. Casas and coworkers (Casas et al., 1999) reported that mitochondrial activity was stimulated by overexpression of p43 (mitochondria-targeted, truncated-TR
), which in turn, stimulated mitochondrial genome transcription of some enzyme units that played a role in the respiratory chain. The p43 protein had the same affinity to T3 as the full-length TR
to bind to the D-loop of two mt-TREs in the mitochondria, leading to mitochondrial protein synthesis (Casas et al., 1999). Their data suggested that p43 bound to mt-TREs as a homodimer because no RXR-isoform in the mitochondrial extract was detected (Casas et al., 1999). Hadzic suggested that the NH2 terminus of TRs plays a role in TR-homodimerization in mitochondria (Hadzic et al., 1998). Together, these studies demonstrated that mitochondrial-targeted TRs could regulate mitochondrial metabolism by initiating transcription. However, our results cannot be accounted for by this mechanism of action. Specifically, transcriptionally inactive TR mutants modulated Ca2+ wave activity with the same efficacy as the wild type, xTRßA1. We confirmed that xRXR
was required for xTRßA1 to transactivate a reporter gene in our system, but more importantly, the presence of xRXR did not affect the ability of xTRßA1 to modulate Ca2+ activity. Thus, we concluded that the mechanism by which T3-activated TRs regulate Ca2+ signaling cannot be attributed to transcription.
Nongenomic effects of various steroid receptors have been reported for mineralocorticoids (Moura and Worcel, 1984; Zhou and Bubien, 2001), glucocorticoids (Borski, 2000; Borski et al., 2002), gonadal steroids (Pietras and Szego, 1975; Wasserman et al., 1980; Lieberherr and Grosse, 1994; Guo et al., 2002a,b; Minshall et al., 2002), vitamin D3 (Sergeev and Rhoten, 1995), and thyroid hormone (Hummerich and Soboll, 1989; Davis and Davis, 1996, 2002; Rojas et al., 2003). Most of these studies proposed the presence of specific membrane-bound receptors for nongenomic effects; however, specific receptors were not cloned or identified. For thyroid hormones in particular, Davis and Davis (2002) suggested that the mechanism of the nongenomic effects of thyroid hormone may not require TRs, and could involve actions of the hormone itself on signal transduction pathway via specific G proteincoupled protein. Recent work by Scanlan et al. (2004) identified an endogenous, rapid-acting derivative of thyroid hormone that is a potent agonist of the G protein-coupled trace amine receptor (TAR1). Activation of TAR1 increased cAMP production, which in turn, would active protein kinase A and phosphorylation of multiple proteins in cells. Our results do not exclude a potential role of second messenger systems in the mechanism of action of T3 on mitochondria. Rather, they demonstrate that classic TRs, those that have long been known to regulate gene transcription, will also acutely regulate mitochondrial activity when bound with T3. Stimulation is dependent on mitochondrial targeting of the TR, but not on its ability to initiate transcription. Together, these observations reveal a nontranscriptional pathway for modulation of intracellular Ca2+ signaling via T3/TR-stimulated mitochondrial metabolism.
The discovery of T3/TR-regulated Ca2+ signaling is potentially important for several reasons. First, any process that acutely regulates intracellular Ca2+ release will impact the multitude of Ca2+-sensitive cellular processes ranging from contractility and secretion to proteolysis and cell death. Second, the ability of a steroid hormone to increase proton pumping provides a rapid method to increase metabolism in response to short-term energy requirements; for example, during increased neuronal activity or during a transient increase in muscle activity. Third, and potentially more importantly, a rapid increase in mitochondrial Ca2+ uptake could protect cells under conditions of stress. Mitochondria have long been recognized for their capacity to sequester large Ca2+ concentrations under pathological conditions (Gunter et al., 1994). The ability to transiently remove Ca2+ from the cytosol could be used to minimize tissue damage after stroke in neuronal tissue or to reduce the instability of cardiac cells after periods of hypoxia. Clearly, the identification of a mitochondrial receptor for thyroid hormone-induced increases in metabolism offers a new pharmacological target from which it will be possible to regulate a broad range of physiological and pathological processes.
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Materials and methods |
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Xenopus TRßA1 was amplified by PCR with primers 5'-gctaggatccatggaagggtatatacccagctacttgg-3' and 5'-atcgaagcttctagtcctcaaacacttccaagaacagtggggg-3' and subcloned into vector pGEM-HeNot between the BamHI and HinDIII sites to create pGEM-HeNot-xTRßA1. Xenopus mutant xTRßA1-NLS had its NLS removed by modifying the sequence from KR to AA. xTRßA1
pBox-NLS had the same NLS modification as well as the pBOX deletion of CEGCK within the DBD. Both mutants were generated by QuikChange site-directed mutagenesis (Stratagene) using pGEM-HeNot-xTRßA1 as a template. The forward primer for xTRßA1NLS was 5'-ggttttggatgacaacgcagctttggcaaaaagaaagc-3' and the reverse complement primer was 5'-gctttctttttgccaaagctgcgttgtcatccaaaacc-3'. For the double mutation, pGEM-HeNot-xTRßA1NLS was used as a template. The forward primer for xTRßA1
pBox-NLS was 5'-gggtatcattatagatgtatcaccggcttttttagaagaactattcag-3' and the reverse compliment primer was 5'-ctgaatagttcttctaaaaaagccggtgatacatctataatgataccc-3'. All mutations were confirmed by nucleotide sequencing (UTHSCSA DNA core facility).
In vitro transcriptions and oocyte protocols
Synthetic mRNA was prepared as described previously (Camacho and Lechleiter, 1995). In brief, the pGEM-HeNot vector containing cDNA template was linearized by a NotI restriction enzyme. From the linearized templates, mRNA was generated using the T7 promoter (MEGAscript; Ambion). Cap analogue, m7G(5')ppp(5") (Ambion) was added to the reaction. The mRNA products were quantified by 1% agarose gel and spectrophotometry. RNase-free synthetic RNAs were resuspended at a concentration of 1.52.0 µg/µl and stored in aliquots of 3 µl at 80°C.
Stage VI oocytes were obtained from adult female Xenopus laevis. After defolliculation, oocytes were incubated in MBS (in mM: 88 NaCl, 1 KCl, 0.41 CaCl2, 0.33 Ca(NO3)2, 0.82 MgSO4, 2.40 NaHCO3, 10 Hepes, pH 7.5) at 18°C. mRNA was injected into the oocytes by a 50-nL bolus using a positive pressure injector (Nanoject; Drummond Scientific Co.). Control oocytes were injected with diethyl pyrocarbonatetreated water. Oocytes were incubated at 18°C for 23 d to allow full expression of proteins in MBS supplemented with antibiotics streptomycin, penicillin, and fungizone (GIBCO-BRL). Media was changed daily. Unhealthy oocytes were discarded daily.
Imaging acquisition and analysis
Ca2+ wave activity was imaged as described previously (Camacho and Lechleiter, 1995). In brief, oocytes were injected with 50 nl of a fluorescent Ca2+ sensitive dye (0.25 mM, Oregon green BAPTA2-cell impermeant; Molecular Probes) and incubated for 3060 min before the experiment. Images were acquired with a confocal laser-scanning microscope (model PCM2000; Nikon) attached to an inverted microscope (model TE200; Nikon) at the rate of 1.5 images/s. We used a 10x 0.45 NA objective (UVFLUOR; Nikon). Each group of mRNA-injected oocytes was randomly assigned into two subgroups, one was exposed to 100 nM of T3 for 10 min and the other was untreated with T3. Ca2+ wave activity was initiated by injecting a 50-nl bolus of 6 µM IP3. The Ca2+ waves were analyzed with ANALYZE software (The Mayo Foundation, Rochester, MN). Statistical significance was calculated by either one-factor ANOVA or a t test as indicated.
was estimated as described previously (Lin and Lechleiter, 2002). In brief, 200 nM TMRE (Molecular Probes) was added to the bath and images were acquired with a 60x 1.4 NA objective on the Nikon PCM2000 custom adapted for two-photon imaging. TMRE was excited at 800 nm using a Ti-sapphire Coherent Mira 900 Laser pumped with a 5W Verdi laser (Coherent Inc.). Laser intensity was attenuated with a neutral-density filter wheel such that no detectable photobleaching of TMRE was observed.
Transcriptional activity assay
The transcriptional activity of TR and mutants were confirmed by using a reporting vector with the thyroid response element (TRE) as a cis-acting enhancer for the SEAP gene (Mercury Pathway Profiling SEAP System2; CLONTECH Laboratories, Inc.). The negative control vector (pSEAP(ve)) lacks the enhancer element, but contains a promoter and SEAP reporter gene. Oocytes in each group were injected with mRNA (0.5 µg) and vector (0.5 µg) as designated, and incubated in 1 ml MBS with 100 nM T3, and/or RA for 3 d. Media was collected and replaced every 24 h for 3 d. Collected media from each group was pooled, concentrated (Amicon ultra 10000 MWCO; Millipore) to 40 µl and run on a 10% SDS-PAGE. Oocyte cytosolic extract from each group was prepared and loaded onto 10% SDS-PAGE at amounts equivalent to 2.5 oocytes per lane. SEAP was detected with polyclonal rabbit antihuman SEAP antibody (Zymed Laboratories, Inc.). HRP-conjugated secondary antibody (Jackson ImmunoResearch Laboratories Inc.) was used and visualized by chemiluminescence (PerkinElmer).
Western blot analysis
Oocytes were washed twice times in homogenization buffer (in mM: 15 Tris-HCl, 140 NaCl, 250 sucrose, 1% Triton X-100, Complete protease inhibitor cocktail) at a concentration of 40 µl/oocyte. Washed oocytes were homogenized and centrifuged at 4,500 g for 15 min at 4°C. The supernatant was collected and loaded at 0.5 oocytes per lane onto 10% SDS-PAGE. TRs and mutants were detected with monoclonal mouse antihuman TRs antibody (MA1-215; Affinity BioReagents, Inc.). xRXR was detected with polyclonal rabbit antihuman RXRs antibody (Sc-774; Santa Cruz Biotechnology, Inc.). HRP-conjugated secondary antibody (Jackson ImmunoResearch Laboratories Inc.) was used and visualized by chemiluminescence (PerkinElmer).
Cytosolic and mitochondrial extract preparations
300 oocytes in each group (water, xTRßA1, rTR1, rTR
1
F) were allowed to express for 3 d and then treated with 100 nM T3 for 15 min at RT. Oocytes were washed twice times with buffer A (in mM: 190 sorbitol, 1 CaCl2, 10 TES, pH 7.4) and resuspended in buffer A at a final volume of 500 µl. Oocytes were sequentially homogenized with a hand-held homogenizer and centrifuged at 1,000 g for 5 min at 4°C. The supernatant was transferred to new tube and centrifuged at 14,000 g for 15 min at 4°C. Supernatant and pellet were collected separately. The pellet, which contained mitochondria, was washed several times with buffer B (in mM: 195 sorbitol, 5 EDTA, 5 TES, pH 7.4) and spun at 1,000 g for 5 min at 4°C to eliminate contaminants. The mitochondrial portion was finally obtained by centrifugation at 14,000 g for 15 min at 4°C. Mitochondria in each group were washed twice by resuspending in buffer B, centrifuged again at 14,000 g for 15 min at 4°C and lysed in the presence of 1% Triton X-100. The cytosolic fraction was centrifuged at 100,000 g for 15 min at 4°C to eliminate contaminating membranes.
O2 consumption assay
A biological O2 monitor (model 5300; YSI Inc.) was used to measure O2 consumption. 200 oocytes in each group were loaded into a 2-ml O2 probe chamber avoiding contact of the oocytes with the O2 probe. 1.5 ml of MBS was added to the chamber and the system was allowed to stabilize for 15 min. The medium was subsequently exchanged with 1.25 ml of fresh MBS solution and O2 consumption was monitored for 30 min. The media was exchanged again with MBS containing 100 nM T3 and O2 consumption was followed for the next 30 min. The slope of O2 levels was calculated before and after the addition of T3.
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Acknowledgments |
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This work was supported by National Institutes of Health grants R01 GM48451 and PO1 AG19316.
Submitted: 2 September 2004
Accepted: 17 September 2004
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References |
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