Abstract
The possibility that several pathways are involved in the multiplicity of thyroid hormone physiological influences led to searches for the occurrence of T3 extra nuclear receptors. The existence of a direct T3 mitochondrial pathway is now well established. The demonstration that TRα1 mRNA encodes not only a nuclear thyroid hormone receptor but also two proteins imported into mitochondria with molecular masses of 43 and 28 kDa has provided new clues to understand the pleiotropic influence of iodinated hormones.
The use of a T3 photo affinity label derivative (T3-PAL) allowed detecting two mitochondrial T3 binding proteins. In association with western blots using antibodies raised against the T3 nuclear receptor TRα1, mitochondrial T3 receptors were identified as truncated TRα1 forms. Import and in organello transcription experiments performed in isolated mitochondria led to the conclusion that p43 is a transcription factor of the mitochondrial genome, inducing changes in the mitochondrial/nuclear crosstalk. In vitro experiments indicated that this T3 mitochondrial pathway affects cell differentiation, apoptosis, and transformation. Generation of transgenic mice demonstrated the involvement of this mitochondrial pathway in the determination of muscle phenotype, glucose metabolism, and thermogenesis.
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References
Wrutniak-Cabello C, Casas F, Rochard P et al (2001) Effets non génomiques des hormones thyroïdiennes. In: Leclère J, Orgiazzi RB, Schlienger JL, Wémeau JL (eds) La thyroïde, des concepts à la pratique clinique, 2nd edn. Elvesier, Amsterdam, p 162
Tata JR, Ernster L, Lindberg O et al (1963) The action of thyroid hormones at the cell level. Biochem J 86:408–428
Sap J, Muñoz A, Damm K et al (1986) The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 324:635–640
Weinberger C, Thompson CC, Ong ES et al (1986) The c-erb-A gene encodes a thyroid hormone receptor. Nature 324:641–646
Lazar MA (1993) Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 14:184–193
Suen CS, Yen PM, Chin WW (1994) In vitro transcriptional studies of the roles of the thyroid hormone (T3) response elements and minimal promoters in T3-stimulated gene transcription. J Biol Chem 269:1314–1322
Glass CK (1994) Differential recognition of target genes by nuclear receptor monomers, dimers and heterodimers. Endocr Rev 15:391–407
Harvey CB, Williams GR (2002) Mechanism of thyroid hormone action. Thyroid 12:441–446
Segal J, Gordon A (1977) The effects of actinomycin D, puromycin, cycloheximide and hydroxyurea on 3′,5,3-triiodo-L-thyronine stimulated 2-deoxy-D-glucose uptake in chick embryo heart cells in vitro. Endocrinology 101:150–156
Segal J (1989) A rapid, extranuclear effect of 3,5,3′-triiodothyronine on sugar uptake by several tissues in the rat in vivo. Evidence for a physiological role for the thyroid hormone action at the level of the plasma membrane. Endocrinology 124:2755–2764
Segal J, Ingbar SH (1982) Specific binding sites for triiodothyronine in the plasma membrane of rat thymocytes. Correlation with biochemical responses. J Clin Invest 70:919–926
Bergh JJ, Lin HY, Lansing L et al (2005) Integrin αvβ3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146:2864–2871
Davis PJ, Davis FB, Cody V (2005) Membrane receptors mediating thyroid hormone action. Trends Endocrinol Metab 16:429–435
Kalyanaraman H, Schwappacher R, Joshua J et al (2014) Nongenomic thyroid hormone signaling occurs through a plasma membrane-localized receptor. Sci Signal 7:ra48
Sterling K, Brenner MA, Sakurada T (1980) Rapid effect of triiodothyronine on the mitochondrial pathway in rat liver in vivo. Science 210:340–342
Sterling K, Brenner MA (1995) Thyroid hormone action: effect of triiodothyronine on mitochondrial adenine nucleotide translocase in vivo and in vitro. Metabolism 34:193–199
Enriquez JA, Fernandez-Silva P, Garrido-Pérez N et al (1999) Direct regulation of mitochondrial RNA synthesis by thyroid hormone. Mol Cell Biol 19:657–670
Goglia F, Torresani J, Bugli P et al (1981) In vitro binding of triiodothyronine to rat liver mitochondria. Pflugers Arch Eur J Physiol 390:120–124
Sterling K, Milch PO (1975) Thyroid hormone binding by a component of mitochondrial membrane. Proc Natl Acad Sci U S A 72:3225–3229
Hashizume K, Ichikawa K (1982) Localization of 3,5,3′-L-triiodothyronine receptor in rat kidney mitochondrial membranes. Biochem Biophys Res Commun 106:920–926
Pascual A, Casanova J, Samuels HH (1982) Photoaffinity labeling of thyroid hormone nuclear receptors in intact cells. J Biol Chem 257:9640–9647
Wrutniak C, Cassar-Malek I, Marchal S et al (1995) A 43-kDa protein related to c-Erb A alpha 1 is located in the mitochondrial matrix of rat liver. J Biol Chem 270:16347–16354
Bigler J, Eisenman RN (1988) c-erbA encodes multiple proteins in chicken erythroid cells. Mol Cell Biol 8:4155–4161
Bigler J, Hokanson W, Eisenman RN (1992) Thyroid hormone receptor transcriptional activity is potentially autoregulated by truncated forms of the receptor. Mol Cell Biol 12:2406–2417
Scheller K, Sekeris CE, Krohne G et al (2000) Localization of glucocorticoid hormone receptors in mitochondria of human cells. Eur J Cell Biol 79:299–307
Yager JD, Chen JQ (2007) Mitochondrial estrogen receptors—new insights into specific functions. Trends Endocrinol Metab 18:89–91
Silvagno F, De Vivo E, Attanasio A et al (2010) Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes. PLoS One 5:e8670
Casas F, Domenjoud L, Rochard P et al (2000) A 45 kDa protein related to PPARgamma2, induced by peroxisome proliferators, is located in the mitochondrial matrix. FEBS Lett 478:4–8
Casas F, Daury L, Grandemange S et al (2003) Endocrine regulation of mitochondrial activity: involvement of truncated RXRalpha and c-Erb Aalpha1 proteins. FASEB J 17:426–436
Carazo A, Levin J, Casas F et al (2012) Protein sequences involved in the mitochondrial import of the 3,5,3′-L-triiodothyronine receptor p43. J Cell Physiol 227:3768–3777
Mavinakere MS, Powers JM, Subramanian KS et al (2012) Multiple novel signals mediate thyroid hormone receptor nuclear import and export. J Biol Chem 287:31280–31297
Von Heijne G, Steppuhn J, Herrmann RG (1989) Domain structure of mitochondrial and chloroplast targeting peptides. Eur J Biochem 180:535–545
Schatz G, Dobberstein B (1996) Common principles of protein translocation across membranes. Science 271:1519–1526
Neupert W (1997) Protein import into mitochondria. Annu Rev Biochem 66:863–917
Pfanner N, Geissler A (2001) Versatility of the mitochondrial protein import machinery. Nat Rev Mol Cell Biol 2:339–349
Casas F, Rochard P, Rodier A et al (1999) A variant form of the nuclear triiodothyronine receptor c-ErbAalpha1 plays a direct role in regulation of mitochondrial RNA synthesis. Mol Cell Biol 19:7913–7924
Wrutniak C, Rochard P, Casas F et al (1998) Physiological importance of the T3 mitochondrial pathway. Ann Acad Sci N Y 839:93–100
Chocron ES, Sayre NL, Holstein D et al (2012) The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism. Mol Endocrinol 26:1117–1128
Poyton RO, McEwen JE (1996) Crosstalk between nuclear and mitochondrial genomes. Annu Rev Biochem 65:563–607
Pizzo P, Drago I, Filadi R et al (2012) Mitochondrial Ca2+ homeostasis: mechanism, role, and tissue specificities. Pflugers Arch 464:3–17
Brookes PS, Yoon Y, Robotham JL et al (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287:C817–C833
Biswas G, Guha M, Avadhani NG (2005) Mitochondria-to-nucleus stress signaling in mammalian cells: nature of nuclear gene targets, transcription regulation, and induced resistance to apoptosis. Gene 354:132–139
Poyton RO, Ball KA, Castello R (2009) Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab 20:332–340
Mazière C, Conte MA, Degonville J et al (1999) Cellular enrichment with polyunsaturated fatty acids induces an oxidative stress and activates the transcription factors AP1 and NFkappaB. Bioch Biophys Res Commun 265:116–122
Dalton TP, Shertzer HG, Puga A (1999) Regulation of gene expression by reactive oxygen. Annu Rev Pharmacol Toxicol 39:67–101
Georgiadi A, Kersten S (2012) Mechanisms of gene regulation by fatty acids. Adv Nutr 3:127–134
Gremlich S, Bonny C, Waeber G et al (1997) Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 272:30261–30269
Ailhaud GP, Abumrad N, Amri EZ et al (1994) A new look at fatty acids as signal-transducing molecules. World Rev Nutr Diet 75:35–45
Grandemange S, Seyer P, Carazo A et al (2005) Stimulation of mitochondrial activity by p43 overexpression induces human dermal fibroblast transformation. Cancer Res 65:4282–4291
Saelim N, John LM, Wu J et al (2004) Non transcriptional modulation of intracellular Ca2+ signaling by ligand stimulated thyroid hormone receptor. J Cell Biol 167:915–924
Seyer P, Grandemange S, Busson M et al (2006) Mitochondrial activity regulates myoblast differentiation by control of c-Myc expression. J Cell Physiol 207:75–86
Miner JH, Wold BJ (1991) c-myc inhibition of MyoD and myogenin-initiated myogenic differentiation. Mol Cell Biol 11:2842–2851
Crescenzi M, Crouch DH, Tato F (1994) Transformation by myc prevents fusion but not biochemical differentiation of C2C12 myoblasts: mechanisms of phenotypic correction in mixed culture with normal cells. J Cell Biol 125:1137–1145
Cabello G, Casas F, Wrutniak-Cabello C (2010) Transcription factors and muscle differentiation. In: Giordano A, Galderesi U (eds) Cell cycle regulation and differentiation in cardiovascular and neuronal system. Springer, New York. https://doi.org/10.1007/978-1-60327-153-0_3
Rochard P, Rodier A, Casas F et al (2000) Mitochondrial activity is involved in the regulation of myoblast differentiation through myogenin expression and activity of myogenic factors. J Biol Chem 275:2733–2744
Kaneko T, Watanabe T, Oishi M (1988) Effect of mitochondrial protein synthesis inhibitors on erythroid differentiation of mouse erythroleukemia (friend) cells. Mol Cell Biol 8:3311–3315
Cordeau-Lossouarn L, Vayssière JL, Larcher JC et al (1991) Mitochondrial maturation during neuronal differentiation in vivo and in vitro. Biol Cell 71:57–65
Seyer P, Grandemange S, Rochard P et al (2011) P43-dependent mitochondrial activity regulates myoblast differentiation and slow myosin isoform expression by control of Calcineurin expression. Exp Cell Res 317:2059–2071
Chin ER, Olson EN, Richardson JA et al (1998) A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type. Genes Dev 12:2499–2509
Saelim N, Holstein D, Chocron ES et al (2007) Inhibition of apoptotic potency by ligand stimulated thyroid hormone receptors located in mitochondria. Apoptosis 12:1781–1794
Casas F, Pessemesse L, Grandemange S et al (2009) Overexpression of the mitochondrial T3 receptor induces skeletal muscle atrophy during aging. PLoS One 4:e5631
Fernandez-Marcos PJ, Auwerx J (2011) Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93:884S–890S
Casas F, Pessemesse L, Grandemange S et al (2008) Overexpression of the mitochondrial T3 receptor p43 induces a shift in skeletal muscle fiber types. PLoS One 3:e2501
Pessemesse L, Schlernitzauer A, Sar C et al (2012) Depletion of the p43 mitochondrial T3 receptor in mice affects skeletal muscle development and activity. FASEB J 26:748–756
Pelletier P, Gauthier K, Sideleva O et al (2008) Mice lacking the thyroid hormone receptor-alpha gene spend more energy in thermogenesis, burn more fat, and are less sensitive to high-fat diet-induced obesity. Endocrinology 149:6471–6486
Bertrand C, Blanchet E, Pessemesse L et al (2013) Mice lacking the p43 mitochondrial T3 receptor become glucose intolerant and insulin resistant during aging. PLoS One 8:e75111
Blanchet E, Bertrand C, Annicotte JS et al (2012) The mitochondrial T3 receptor p43 regulates insulin secretion and glucose homeostasis. FASEB J 26:40–50
Bertrand-Gaday C, Pessemesse L, Cabello G et al (2016) Temperature homeostasis in mice lacking the p43 mitochondrial T3 receptor. FEBS Lett 590:982–991
Fleischer S, Kervina M (1974) Subcellular fractionation of rat liver. Methods Enzymol 31:6–41
Horowitz ZD, Samuels HH (1988) Thyroid receptor. In: Gronemeyer H (ed) Affinity labelling and cloning of steroid and thyroid hormone receptors. Ellis Horwood Ltd, Chichester, pp p79–p83
Ostronoff LK, Izquierdo JM, Enríquez JA, Montoya J, Cuezva JM (1996) Transient activation of mitochondrial translation regulates the expression of the mitochondrial genome during mammalian mitochondrial differentiation. Biochem J 316:183–191
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
Komiya T, Mihara K (1996) Protein import into mammalian mitochondria. Characterization of the intermediates along the import pathway of the precursor into the matrix. J Biol chem 271:22105–22110
Ragan CI, Wilson MT, Darley-Usmar VM et al (1987) Sub-fractionation of mitochondria and isolation of the proteins of oxidative phosphorylation. In: Darley-Usmar VM, Rickwood D, Wilson MT (eds) Mitochondria, a practical approach. IRL Press, Washington, DC, pp 79–112
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Wrutniak-Cabello, C., Casas, F., Cabello, G. (2018). Thyroid Hormone Action: The p43 Mitochondrial Pathway. In: Plateroti, M., Samarut, J. (eds) Thyroid Hormone Nuclear Receptor. Methods in Molecular Biology, vol 1801. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7902-8_14
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DOI: https://doi.org/10.1007/978-1-4939-7902-8_14
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