A 43-kDa Protein Related to c-Erb A α1 Is Located in the Mitochondrial Matrix of Rat LiverIn order to characterize Sterling's triiodothyronine (T3) mitochondrial receptor using photoaffinity labeling, we observed two specific T3-binding proteins in the inner membrane (28 kDa) and in the matrix (43 kDa) of rat liver mitochondria. Western blots and immunoprecipitation using antibodies raised against the T3-binding domain of the T3 nuclear receptor c-Erb A α1 indicated that at least the 43-kDa protein was c-Erb A α1-related. In addition, gel mobility shift assays demonstrated the occurrence of a c-Erb A α1-related mitochondrial protein that specifically binds to a natural or a palindromic thyroid-responsive element. Moreover, this protein specifically binds to a direct repeat 2 sequence located in the D-loop of the mitochondrial genome. Furthermore, electron microscopy studies allowed the direct observation of a c-Erb A-related protein in mitochondria. Lastly, the relative amounts of the 43-kDa protein related to c-Erb A α1 were in good correlation with the known mitochondrial mass in three typical tissues. Interestingly, expression of a truncated form of the c-Erb A α1 nuclear receptor in CV1 cells was associated with a mitochondrial localization and a stimulation of mitochondrial activity. These results supply evidence of the localization of a member of the nuclear receptor superfamily in the mitochondrial matrix involved in the regulation of mitochondrial activity that could act as a mitochondrial T3-dependent transcription factor. In order to characterize Sterling's triiodothyronine (T3) mitochondrial receptor using photoaffinity labeling, we observed two specific T3-binding proteins in the inner membrane (28 kDa) and in the matrix (43 kDa) of rat liver mitochondria. Western blots and immunoprecipitation using antibodies raised against the T3-binding domain of the T3 nuclear receptor c-Erb A α1 indicated that at least the 43-kDa protein was c-Erb A α1-related. In addition, gel mobility shift assays demonstrated the occurrence of a c-Erb A α1-related mitochondrial protein that specifically binds to a natural or a palindromic thyroid-responsive element. Moreover, this protein specifically binds to a direct repeat 2 sequence located in the D-loop of the mitochondrial genome. Furthermore, electron microscopy studies allowed the direct observation of a c-Erb A-related protein in mitochondria. Lastly, the relative amounts of the 43-kDa protein related to c-Erb A α1 were in good correlation with the known mitochondrial mass in three typical tissues. Interestingly, expression of a truncated form of the c-Erb A α1 nuclear receptor in CV1 cells was associated with a mitochondrial localization and a stimulation of mitochondrial activity. These results supply evidence of the localization of a member of the nuclear receptor superfamily in the mitochondrial matrix involved in the regulation of mitochondrial activity that could act as a mitochondrial T3-dependent transcription factor. The regulation of mitochondrial function by thyroid hormone is well documented. Triiodothyronine (T3)1( 1The abbreviations used are: T3triiodothyronineT3-PALT3-photoaffinity labelingT3REthyroid-responsive elementPBSphosphate-buffered salineCREBcAMP-responsive element-binding proteinDR2direct repeat 2.) increases the number of mitochondria (Gustafsson et al., 1965Gustafsson R. Tata J.R. Lindberg J. Ernster L. J. Cell Biol. 1965; 26: 555-578Crossref PubMed Scopus (133) Google Scholar; Kadenbach, 1966Kadenbach B. Targer J.M. Papa S. Quagliariello E. Slater E.C. Regulation of Metabolic Processes in Mitochondria. Elsevier Science Publishers B.V., Amsterdam1966: 508-517Google Scholar; Jakovilcic et al., 1978Jakovilcic S. Swift H.H. Gross N.J. Rabinowitz R. J. Cell Biol. 1978; 77: 887-901Crossref PubMed Scopus (81) Google Scholar) and the mitochondrial protein synthesis (Mutvei et al., 1989aMutvei A. Husman B. Andersson G. Nelson B.D. Acta Endocrinol. 1989; 121: 223-228Crossref PubMed Scopus (43) Google Scholar). Therefore, this hormone is considered to be the major regulator of mammalian mitochondrial biogenesis (Mutvei et al., 1989aMutvei A. Husman B. Andersson G. Nelson B.D. Acta Endocrinol. 1989; 121: 223-228Crossref PubMed Scopus (43) Google Scholar). T3 also stimulates the mitochondrial metabolism (Soboll et al., 1992Soboll S. Horst C. Hummerich H. Schumacher J.P. Seitz H.J. Biochem. J. 1992; 281: 171-173Crossref PubMed Scopus (18) Google Scholar) and particularly oxidative phosphorylations (Sterling et al., 1977Sterling K. Milch P.O. Brenner M.A. Lazarus J.H. Science. 1977; 197: 996-999Crossref PubMed Scopus (128) Google Scholar, Sterling et al., 1980Sterling K. Brenner M.A. Sakurada T. Science. 1980; 210: 340-343Crossref PubMed Scopus (93) Google Scholar). More recently, De Duve, 1967De Duve C. Methods Enzymol. 1967; 10: 7-18Crossref Scopus (19) Google Scholar have shown that thyroid hormone could control state 3 respiration. Some of these effects could involve the activation of mitochondrial gene transcription induced by T3 (De Leo et al., 1976De Leo T. Di Meo S. Barletta A. Martino G. Goglia F. Pfluegers Arch. Eur. J. Physiol. 1976; 366: 73-77Crossref PubMed Scopus (18) Google Scholar; Martino et al., 1986Martino G. Covello C. De Giovanni R. Filipelli R. Pitrelli G. Mol. Biol. Rep. 1986; 11: 205-211Crossref PubMed Scopus (15) Google Scholar; Mutvei et al., 1989bMutvei A. Kuzela S. Nelson B.D. Eur. J. Biochem. 1989; 180: 235-240Crossref PubMed Scopus (84) Google Scholar) and the increase in the mRNA of mitochondrial cytochrome c oxidase subunit levels (Van Itallie, 1990). triiodothyronine T3-photoaffinity labeling thyroid-responsive element phosphate-buffered saline cAMP-responsive element-binding protein direct repeat 2. In addition, an early mitochondrial T3 uptake after [125I]T3 administration has been reported in electron microscopy studies (Sterling et al., 1984bSterling K. Campbell G.A. Taliadouros G.S. Nunez E.A. Cell Tissue Res. 1984; 236: 321-325Crossref PubMed Scopus (30) Google Scholar). In agreement with this observation, evidence of at least one high affinity T3-binding site was provided by [125I]T3 binding studies in the mitochondria (Sterling and Milch, 1975Sterling K. Milch P.O. Proc. Natl. Acad. Sci U. S. A. 1975; 72: 3225-3229Crossref PubMed Scopus (110) Google Scholar; Goglia et al., 1981Goglia F. Torresani J. Bugli P. Barletta A. Liverini G. Pfluegers Arch. Eur. J. Physiol. 1981; 390: 120-124Crossref PubMed Scopus (56) Google Scholar; Hashizume and Ichikawa, 1982Hashizume K. Ichikawa K. Biochem. Biophys. Res. Commun. 1982; 106: 920-926Crossref PubMed Scopus (51) Google Scholar), suggesting that a T3 mitochondrial receptor (Ka = 1010M-1; molecular mass = 28 kDa) is located in the organelle's inner membrane (Sterling et al., 1984bSterling K. Campbell G.A. Taliadouros G.S. Nunez E.A. Cell Tissue Res. 1984; 236: 321-325Crossref PubMed Scopus (30) Google Scholar). However, the involvement of a direct pathway in the mitochondrial action of T3 is still debated. Therefore, the characterization of the mitochondrial T3 receptor could be an important tool to verify the existence of such a pathway. The ADP/ATP translocator has been proposed as a putative T3 mitochondrial receptor (Sterling, 1986). Unfortunately, in agreement with Rasmussen et al., 1989Rasmussen U.B. Köhrle J. Rokos H. Hesch R.D. FEBS Lett. 1989; 255: 385-390Crossref PubMed Scopus (17) Google Scholar, we were unable to observe any T3 binding activity of this protein, neither in mitochondria nor by testing the purified protein (kindly provided by Dr. Brandolin, Grenoble, France). Nuclear T3 receptors are encoded by two different loci leading to the synthesis of three T3-binding proteins (c-Erb A β1, β2, and α1) sharing homology in the DNA-binding and ligand-binding domains. In addition to the full-length 46-kDa c-Erb A α1 protein, Bigler and Eisenman(1988) have reported the occurrence of several smaller size cellular c-Erb A α proteins in chicken erythroid cells, some of which display an extranuclear location. On the basis of these observations, we searched for the presence of protein(s) related to c-Erb A in mitochondria, and we report here the existence in the mitochondrial matrix of a 43-kDa protein related to c-Erb A α1 with thyroid-responsive element (T3RE) and T3 binding activities. Male Wistar rats (body weight, 200 g) were injected with Triton WR 1339 (75 mg of Triton/100 g of body weight in order to reduce lysosome density) 4 days before euthanasia. Animals were sacrificed after a 16-h period of food deprivation to reduce cellular stocks of lipids and glycogen. Liver mitochondria were prepared by differential centrifugations and purified using a sucrose gradient (1.02/1.68 M) according to Fleischer and Kervina(1974) and Szczesna-Kaczmarek(1990). Mitoplast, inner membrane, outer membrane, and matrix fractions were obtained using digitonin and Lubrol, as described previously by Greenawalt(1974). Lysosome, microsome, plasma membrane, and nuclei fractions were obtained according to Fleischer and Kervina(1974). The purity of mitochondrial preparations was tested by measuring the specific activities of acid phosphatase (lysosomes; De Duve(1967)), glucose-6-phosphatase (microsomes; Morré(1971)), and 5′-nucleotidase (plasma membranes; Morré(1971)). Monoamine oxidase (outer membrane; Ragan et al., 1987Ragan C.I. Wilson M.T. Darley-Usmar V.M. Lowe P.M. Darley-Usmar V.M. Rickwood D. Wilson M.T. Mitochondria: A Practical Approach. IRL Press, Oxford1987: 79-112Google Scholar), malate dehydrogenase (matrix; Ragan et al., 1987Ragan C.I. Wilson M.T. Darley-Usmar V.M. Lowe P.M. Darley-Usmar V.M. Rickwood D. Wilson M.T. Mitochondria: A Practical Approach. IRL Press, Oxford1987: 79-112Google Scholar), and succinate dehydrogenase (inner membrane; Morré, 1971Morré D.J. Methods Enzymol. 1971; 22: 130-145Google Scholar) were also measured to test the submitochondrial fractions (data not shown). Nuclear contaminations were assessed by Western blots of specific nuclear proteins (lamin A, CREB, and c-Erb A β). Lamin A was detected using an antibody kindly provided by Höger et al., 1991Höger T.I. Grund C. Franke W.W. Krohne G. Europ. J. Cell Biol. 1991; 54: 150-156PubMed Google Scholar and revealed using a second antibody linked to alkaline phosphatase. c-Erb A β was detected using RHTII antiserum and revealed by 125I-protein A. CREB was detected using anti-rat CREB (rabbit polyclonal antiserum, UBI, Lake Placid, NY) and revealed using the ECL kit (Amersham Corp.). Electron micrograph was performed on purified rat liver mitochondria. The pellet was fixed by 1% glutaraldehyde/1% paraformaldehyde in phosphate buffer, washed in PBS, postfixed in OsO4, and embedded in Epon. T3-binding proteins were detected using a [125I]T3 photoaffinity label derivative (T3-PAL), which covalently binds to these proteins after ultraviolet irradiation. [125I]T3-PAL was synthetized and protein labeling was performed according to Horowitz and Samuels(1988). The 100-μg protein samples were electrophoresed in a SDS-10% polyacrylamide gel (Laemmli, 1970) and autoradiographed. T3-PAL labeling was performed without and with a previous incubation of mitochondrial proteins with a 1000-fold molar excess of cold T3-PAL in order to assess labeling specificity. Western blots of mitochondrial proteins were performed using two different rabbit antisera (IRS 21 and RHTII). IRS 21 is directed against a bacterially expressed protein containing 99 amino acid residues of MS2 polymerase fused to the 96 amino acid residues of the hormone-binding domain of the human c-Erb A α1 nuclear T3 receptor (Sap et al., 1986Sap J. Munoz A. Damm K. Goldberg Y. Ghysdael J. Leutz A. Beug H. Vennström B. Nature. 1986; 324: 635-640Crossref PubMed Scopus (1021) Google Scholar). RHTII antiserum is raised against the following amino acid sequence: Glu-Cys-Pro-Thr-Glu-Leu-Phe-Pro-Pro-Leu-Phe-Leu-Glu-Val-Phe-Glu (399-414 of c-Erb A α1 xenopus receptor, 392-407 of c-Erb A α1 chicken receptor, 391-406 of c-Erb A α1 rat receptor, and 440-455 of c-Erb A β rat receptor). Immunoprecipitation of [125I]T3-PAL-binding proteins was performed with IRS 21 antiserum (Sambrook et al., 1989Sambrook J. Fritsch E.F. Maniatis T. Molecular Coning: A Scholar). to gel mobility shift purified mitochondria were at for with two of A of the g for the was in with and was a in The was washed with and with containing proteins were and by with the pellet was and in mobility shift assays were performed according to et al., G. Nature. 1989; PubMed Scopus Google Scholar using a palindromic as a of binding was tested by with 200 of cold palindromic or with a of a unable to nuclear T3 receptors A natural on the sequence of the gene et al., C. C. T. J. G. J. H. Beug H. 1991; PubMed Scopus Google Scholar) was also were performed using a to a direct repeat sequence et al., F. V.M. J. Biol. PubMed Google Scholar) observed in the rat D-loop according to the sequence of the mitochondrial et al., G. G. De G. Quagliariello C. E. C. J. Mol. 1989; PubMed Scopus Google Scholar). Electron microscopy was performed on Wistar rat liver preparations and were fixed with in phosphate buffer, for at The fixed were with were prepared and on electron were washed with phosphate buffer, containing and and with RHTII antiserum in for the the were for with antiserum in buffer, containing and were with 1% and in a electron CV1 cells were in with were washed in and fixed for in prepared paraformaldehyde with The cells were washed in and in for at were in for and washed in cells were for in and in a of rabbit RHTII antiserum and antibody against mitochondria in for for 3 in with cells were with a antibody and a a 3 in with were and using a CV1 cells truncated A protein were obtained by (kindly provided by Bigler and Bigler et al., J. Mol. Biol. 1992; PubMed Scopus Google Scholar). to the cells were at was cells by the with as a were in the presence of activity was observed in cells by of uptake et al., Proc. Natl. Acad. U. S. A. 1980; 77: PubMed Scopus Google Scholar) as a of mitochondrial membrane Cell Biol. PubMed Scopus Google Scholar) and of cytochrome oxidase activity and A. Methods Enzymol. 1967; 10: Scopus Google Scholar). Electron microscopy not the occurrence of in preparations of specific activities of acid and 5′-nucleotidase that contaminations by microsome, and membrane proteins were and Moreover, a protein, A, was not detected by Western in and 200 of mitochondrial was in of nuclear proteins the nuclear transcription CREB was detected in of nuclear proteins and was on the of in of nuclear was not detected in and 200 of mitochondrial proteins In addition, RHTII antiserum the c-Erb A α1 and β of T3 nuclear in mitochondrial we were unable to c-Erb A the major in liver nuclei searched for T3-binding proteins in purified mitochondrial preparations rat In three proteins were by [125I]T3-PAL labeling with molecular mass in gel of and 28 In agreement with the of Rasmussen et al., 1989Rasmussen U.B. Köhrle J. Rokos H. Hesch R.D. FEBS Lett. 1989; 255: 385-390Crossref PubMed Scopus (17) Google Scholar, a T3-PAL could not be detected in the that the ADP/ATP translocator is to T3 Furthermore, a purified of the ADP/ATP translocator could not be after incubation in the presence of [125I]T3-PAL (data not shown). of the and proteins is is with a 1000-fold excess of T3-PAL proteins and 28 kDa) were observed by of mitochondrial using IRS a specific A α antibody IRS 21 is directed against a bacterially expressed MS2 A α of c-Erb A α IRS 21 antibody with or the of an antibody directed against the domain of the protein indicated that antibody binding to the protein was not specific In addition, Western performed with RHTII antiserum specifically detected a 43-kDa protein in mitochondrial preparations mitochondrial we that proteins were detected by T3-PAL labeling (data not and Western blots (IRS in the the protein was for the in the inner membrane, the 43-kDa protein a major localization in the relative amounts could be detected in the inner membrane Interestingly, Western blots performed with RHTII antiserum also detected a 43-kDa protein in the mitochondrial matrix by Western blots (IRS to the 43-kDa protein on microsome, membrane, and nuclear preparations a specific mitochondrial IRS 21 antibody and mitochondrial we were to a 43-kDa not the antibody was with an excess of the A α protein Therefore, the 43-kDa T3-binding protein was to be related to the 43-kDa protein detected by Western In agreement with this of using RHTII antibody in electron microscopy we have observed a specific liver mitochondrial labeling, which not using the or the c-Erb A antiserum In order to the mitochondrial 43-kDa protein and the c-Erb A α1 nuclear receptor, we the binding of the mitochondrial The 43-kDa mitochondrial protein to and to (data not shown). mobility shift assays performed with mitochondrial preparations purified on that a protein or a protein binds to a palindromic A and and a natural on the chicken gene (data not shown). excess of cold was to binding to the a molar excess of a unable to T3 receptors of the binding Moreover, in to antisera against MS2 and rat ADP/ATP IRS 21 and RHTII antisera the observed for mitochondrial RHTII antiserum the 43-kDa protein in purified mitochondrial these results that the 43-kDa protein also homology in the DNA-binding domain with the nuclear T3 Interestingly, a was observed after of mitochondrial with a sequence located in the D-loop of the rat mitochondrial indicated that the 43-kDa protein binds to a specific sequence in the D-loop which the and is not Sterling et al., 1977Sterling K. Milch P.O. Brenner M.A. Lazarus J.H. Science. 1977; 197: 996-999Crossref PubMed Scopus (128) Google Scholar reported the of mitochondrial T3 receptors in rat we performed photoaffinity labeling and Western blots of rat mitochondrial shown in the 43-kDa protein was not detected in these have the amounts of the 43-kDa protein in mitochondria obtained three in mitochondrial and in was performed using purified mitochondria in which and are that the relative mitochondrial amounts of the 43-kDa protein are in in liver and are in liver in Therefore, a the mitochondrial mass and the of the 43-kDa protein in the suggesting an important mitochondrial function for this the 43-kDa protein homology in the and T3-binding with the nuclear T3 the molecular weight of the mitochondrial protein could be by of the or of the domain of c-Erb A α1 However, et al., K. S. Proc. Natl. Acad. U. S. A. 1992; PubMed Scopus Google Scholar have reported that of the T3 binding activity of the Therefore, using the we in CV1 cells a truncated c-Erb A α1 protein the domain of the nuclear Interestingly, we observed a increase in mitochondrial by RHTII antibody with control cells with the that the protein a major mitochondrial location. Lastly, of the truncated protein induced a stimulation of uptake and cytochrome oxidase activity these indicated that a mitochondrial truncated c-Erb A α1 protein the mitochondrial T3-binding proteins the results of the Sterling reported the presence of a T3-binding protein in the mitochondrial inner In addition, we that a 43-kDa T3-binding protein is in the mitochondrial binding site was not observed by the Sterling leading to the of a mitochondrial receptor were performed using inner membrane preparations after matrix proteins (Sterling et al., K. Campbell G.A. Brenner M.A. Acta Endocrinol. 1984; PubMed Google Scholar). Furthermore, we report here that at least one mitochondrial T3-binding protein is related to c-Erb nuclear these T3-binding we also observed a protein not related to c-Erb A nuclear observed by T3-PAL binding (data not that was also detected in microsome, plasma membrane, and lysosome a specific mitochondrial results the T3-binding protein are not the by IRS 21 and we were unable to this protein by IRS 21 and to by RHTII However, these could be by the amounts of the protein mitochondria. the mitochondrial 43-kDa protein is related to the c-Erb A α1 nuclear raised against two different amino acid of the T3-binding domain of c-Erb A specifically this protein in the Moreover, a 43-kDa T3-binding protein is specifically by IRS 21 Lastly, gel that this mitochondrial protein binds to of that this protein homology in the binding and T3-binding with c-Erb A nuclear The of a protein related to c-Erb A α1 in the is not the of of preparations by nuclei or of by microsome, and membrane proteins were as by of specific proteins A and CREB were not detected in mitochondrial RHTII antibody c-Erb A α1 and β the β form is at least the α1 form in rat liver nuclei et al., J.H. J. Biol. 1992; PubMed Google Scholar; et al., C. J.H. 1992; PubMed Scopus Google Scholar), we were unable to c-Erb A β in mitochondrial the localization of a c-Erb A protein the was the of nuclear a major β form be by Western the to the 43-kDa protein in mitochondrial of mitochondria with not the 43-kDa in Western (data not shown). In electron microscopy studies direct evidence of the presence of a protein related to c-Erb A in the the 43-kDa protein related to c-Erb A α1 a specific mitochondrial Interestingly, we observed that the T3-binding 43-kDa protein related to c-Erb A α1 was not in rat mitochondria, in agreement with the previously reported of T3 receptors in these mitochondria (Sterling et al., 1977Sterling K. Milch P.O. Brenner M.A. Lazarus J.H. Science. 1977; 197: 996-999Crossref PubMed Scopus (128) Google Scholar). In addition, the the amounts of this protein the and the mitochondrial mass of three a involvement of the 43-kDa protein in the regulation of a (Gustafsson et al., 1965Gustafsson R. Tata J.R. Lindberg J. Ernster L. J. Cell Biol. 1965; 26: 555-578Crossref PubMed Scopus (133) Google Scholar; Kadenbach, 1966Kadenbach B. Targer J.M. Papa S. Quagliariello E. Slater E.C. Regulation of Metabolic Processes in Mitochondria. Elsevier Science Publishers B.V., Amsterdam1966: 508-517Google Scholar; Jakovilcic et al., 1978Jakovilcic S. Swift H.H. Gross N.J. Rabinowitz R. J. Cell Biol. 1978; 77: 887-901Crossref PubMed Scopus (81) Google Scholar). these that the 43-kDa protein is a putative T3 mitochondrial is well by the observation that of a truncated c-Erb A α1 protein a mitochondrial localization induced a stimulation of the activity assessed by uptake and cytochrome oxidase a well known of T3 at the mitochondrial The and function of this protein is the sequence of the mitochondrial in several the 43-kDa protein related to c-Erb A α1 is encoded by a nuclear gene and is the different A have been in c-Erb A β1, β2, and have been that could to the specific synthesis of a 43-kDa c-Erb A α1 polymerase in rat liver we were also unable to A α1 that the 46-kDa protein (data not shown). the of such a mRNA could not be is raised by the observation of et al., 1986Sap J. Munoz A. Damm K. Goldberg Y. Ghysdael J. Leutz A. Beug H. Vennström B. Nature. 1986; 324: 635-640Crossref PubMed Scopus (1021) Google Scholar that in of a chicken A α1 mRNA to two major proteins with molecular mass of and The was observed by these after of the A α1 in chicken Therefore, the A α1 mRNA two is by the of several c-Erb A α1 proteins in cells and and the observation that some of have an extranuclear In addition, Bigler et al., J. Mol. Biol. 1992; PubMed Scopus Google Scholar reported that the smaller receptor are by at in full-length A α1 Therefore, we that the mitochondrial T3-binding protein could be the of the mRNA A α1 using an In agreement with this we observed that of a truncated c-Erb A α1 protein to the obtained by of the to the synthesis of a mitochondrial protein a stimulation of mitochondrial activity. Interestingly, the 43-kDa T3-binding protein is in the mitochondrial matrix and is in with mitochondrial studies reported that T3 stimulates mitochondrial gene transcription (De Leo et al., 1976De Leo T. Di Meo S. Barletta A. Martino G. Goglia F. Pfluegers Arch. Eur. J. Physiol. 1976; 366: 73-77Crossref PubMed Scopus (18) Google Scholar; Martino et al., 1986Martino G. Covello C. De Giovanni R. Filipelli R. Pitrelli G. Mol. Biol. Rep. 1986; 11: 205-211Crossref PubMed Scopus (15) Google Scholar; Mutvei et al., 1989bMutvei A. Kuzela S. Nelson B.D. Eur. J. Biochem. 1989; 180: 235-240Crossref PubMed Scopus (84) Google Scholar). have shown that this 43-kDa protein is related to the c-Erb A α1 nuclear receptor, a well known T3-dependent transcription factor. protein a binding activity and particularly is to to a specific sequence of the mitochondrial Therefore, could be proposed that the 43-kDa T3-binding protein could be the transcription in the In the presence of a T3 mitochondrial receptor, which has the truncated form of the T3 nuclear receptor c-Erb A α1 in the mitochondrial which could act as a T3-dependent transcription factor. could the specific action of thyroid hormone on the mitochondria, particularly the stimulation of mitochondrial gene transcription induced by Dr. Bigler and Dr. for the of the and Dr. and Dr. for the of purified ADP/ATP translocator and ADP/ATP translocator antibody and for of the