Abstract
We recently reported that shortened thyroid hormone receptor isoforms (TRs) can target mitochondria and acutely modulate inositol 1,4,5 trisphosphate (IP3)-mediated Ca2+ signaling when activated by thyroid hormone 3,5,3′-tri-iodothyronine (T3). Stimulation occurs via an increase in mitochondrial metabolism that is independent of transcriptional activity. Here, we present evidence that T3-bound xTRβA1s inhibit apoptotic activity mediated by cytochrome c release. An assay for apoptotic potency was modified to measure the ability of Xenopus oocyte extracts to induce morphological changes in isolated liver nuclei. Apoptotic potency was significantly decreased when oocyte extract was prepared from xTRβA1 expressing oocytes and treated with T3. The ability of T3 treatment to inhibit apoptosis was dependent on the expression of xTRβA1s in the mitochondrial fraction, not in the cytosolic fraction. T3 treatment also increased the membrane potential of isolated mitochondria prepared from oocytes expressing xTRβA1s but not from wildtype controls. We conclude that T3 acutely regulates cytochrome c release in a potential dependent manner by activating TRs located within mitochondria.
Similar content being viewed by others
Abbreviations
- Ca2+ :
-
Calcium
- IP3 :
-
Inositol 1,4,5-trisphosphate
- T3 :
-
3,5,3′-tri-iodothyronine
- TRs:
-
Thyroid receptors
- MBS:
-
Modified barth’s solution
- ΔΨ:
-
Mitochondrial membrane potential
- DEPC:
-
Diethyl pyrocarbonate
References
Ichikawa K, Hashizume K (1995) Thyroid hormone action in the cell. Endocr J 42:131–140
Nagai R, Zarain-Herzberg A, Brandl CJ, Fujii J, Tada M, MacLennan DH, Alpert NR, Periasamy M (1989) Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone. Proc Natl Acad Sci USA 86:2966–2970
Oppenheimer JH, Schwartz HL, Mariash CN, Kinlaw WB, Wong NC, Freake HC (1987) Advances in our understanding of thyroid hormone action at the cellular level. Endocr Rev 8:288–308
Abbaticchio G, Giorgino R, Gentile FM, Cassano A, Gattuccio F, Orlando G, Ianni A (1981) Hormones in the seminal fluid. The transport proteins of the thyroid hormones. Acta Eur Fertil 12:307–311
Oppenheimer JH, Schwartz HL, Strait KA (1994) Thyroid hormone action 1994: the plot thickens. Eur J Endocrinol 130:15–24
Kawahara A, Baker BS, Tata JR (1991) Developmental and regional expression of thyroid hormone receptor genes during Xenopus metamorphosis. Development 112:933–943
Soboll S (1993) Long-term and short-term changes in mitochondrial parameters by thyroid hormones. Biochem Soc Trans 21(Pt 3):799–803
Iglesias T, Caubin J, Zaballos A, Bernal J, Munoz A (1995) Identification of the mitochondrial NADH dehydrogenase subunit 3 (ND3) as a thyroid hormone regulated gene by whole genome PCR analysis. Biochem Biophys Res Commun 210:995–1000
Wrutniak C, Cassar-Malek I, Marchal S, Rascle A, Heusser S, Keller JM, Flechon J, Dauca M, Samarut J, Ghysdael J 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
Das AM, Harris DA (1991) Control of mitochondrial ATP synthase in rat cardiomyocytes: effects of thyroid hormone. Biochim Biophys Acta 1096:284–290
Meehan J, Kennedy JM (1997) Influence of thyroid hormone on the tissue-specific expression of cytochrome c oxidase isoforms during cardiac development. Biochem J 327(Pt 1):155–160
Schonfeld P, Wieckowski MR, Wojtczak L (1997) Thyroid hormone-induced expression of the ADP/ATP carrier and its effect on fatty acid-induced uncoupling of oxidative phosphorylation. FEBS Lett 416:19–22
Soboll S (1993) Thyroid hormone action on mitochondrial energy transfer. BBABIO 43862:1–16
Upadhyay G, Singh R, Kumar A, Kumar S, Kapoor A, Godbole MM (2004) Severe hyperthyroidism induces mitochondria-mediated apoptosis in rat liver. Hepatology 39:1120–1130
Singh R, Upadhyay G, Godbole MM (2003) Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development. J Endocrinol 176:321–329
Xiao Q, Nikodem VM (1998) Apoptosis in the developing cerebellum of the thyroid hormone deficient rat. Front Biosci 3:A52–A57
Ichikawa K, Hashizume K (1995) Thyroid hormone action in the cell. Endocr J 42:131–140
Oppenheimer JH, Schwartz HL, Strait KA (1994) Thyroid hormone action 1994: the plot thickens. Eur J Endocrinol 130:15–24
Lazar MA (1993) Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 14:184–193
Ardail D, Lerme F, Puymirat J, Morel G (1993) Evidence for the presence of α and β-related T3 receptors in rat liver mitochondria. Eur J Cell Biol 62:105–113
Casas F, Rochard P, Rodier A, Cassar-Malek I, Marchal-Victorion S, Wiesner RJ, Cabello G, Wrutniak C (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
Shi YB, Sachs LM, Jones P, Li Q, Ishizuya-Oka A (1998) Thyroid hormone regulation of Xenopus laevis metamorphosis: functions of thyroid hormone receptors and roles of extracellular matrix remodeling. Wound Repair Regen 6:314–322
Sachs LM, Damjanovski S, Jones PL, Li Q, Amano T, Ueda S, Shi YB, Ishizuya-Oka A (2000) Dual functions of thyroid hormone receptors during Xenopus development. Comp Biochem Physiol B Biochem Mol Biol 126:199–211
Tata JR (1993) Gene expression during metamorphosis: an ideal model for post-embryonic development. Bioessays 15:239–248
Xu Q, Baker BS, Tata JR (1993) Developmental and hormonal regulation of the Xenopus liver-type arginase gene. Eur J Biochem 211:891–898
Yaoita Y, Nakajima K (1997) Induction of apoptosis and CPP32 expression by thyroid hormone in a myoblastic cell line derived from tadpole tail. J Biol Chem 272:5122–5127
Hara M, Suzuki S, Mori J, Yamashita K, Kumagai M, Sakuma T, Kakizawa T, Takeda T, Miyamoto T, Ichikawa K, Hashizume K (2000) Thyroid hormone regulation of apoptosis induced by retinoic acid in promyeloleukemic HL-60 cells: studies with retinoic acid receptor-specific and retinoid × receptor-specific ligands. Thyroid 10:1023–1034
Kalderon B, Hermesh O, Bar-Tana J (1995) Mitochondrial permeability transition is induced by in vivo thyroid hormone treatment. Endocrinology 136:3552–3556
Sterling K, Brenner MA, Sakurada T (1980) Rapid effect of triiodothyronine on the mitochondrial pathway in rat liver in vivo. Science 210:340–342
Crespo-Armas A, Mowbray J (1987) The rapid alteration by tri-iodo-l-thyronine in vivo of both the ADP/O ratio and the apparent H+/O ratio in hypothyroid-rat liver mitochondria. Biochem J 241:657–661
Saelim N, John LM, Wu J, Park JS, Bai Y, Camacho P, Lechleiter JD (2004) Nontranscriptional modulation of intracellular Ca2+ signaling by ligand stimulated thyroid hormone receptor. J Cell Biol 167:915–924
Beato M, Klug J (2000) Steroid hormone receptors: an update. Hum Reprod Update 6:225–236
von Ahsen O, Newmeyer DD (2000) Cell-free apoptosis in Xenopus laevis egg extracts. Methods Enzymol 322:183–198
Lin DT, Lechleiter JD (2002) Mitochondrial targeted cyclophilin D protects cells from cell death by peptidyl prolyl isomerization. J Biol Chem 277:31134–31141
Newmeyer DD, Farschon DM, Reed JC (1994) Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 79:353–364
Camacho P, Lechleiter JD (2000) Xenopus oocytes as a tool in calcium signaling research. In: Putney J (ed) Methods in calcium signaling research. CRC Press LLC, chapter 6, pp. 157–181
Smith LD, Xu WL, Varnold RL (1991) Oogenesis and oocyte isolation. Methods Cell Biol 36:45–60
Heasman J, Holwill S, Wylie CC (1991) Fertilization of cultured Xenopus oocytes and use in studies of maternally inherited molecules. In: Kay BK, Peng HB (eds) Xenopus laevis: practical uses in cell and molecular biology, vol 36. Academic Press, Inc., San Diego, pp 213–230
Lehmann JM, Zhang XK, Graupner G, Lee MO, Hermann T, Hoffmann B, Pfahl M (1993) Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching. Mol Cell Biol 13:7698–7707
von Ahsen O, Newmeyer DD (2000) Cell-free apoptosis in Xenopus laevis egg extracts. Methods Enzymol 322:183–198
Newmeyer DD, Farschon DM, Reed JC (1994) Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 79:353–364
Nutt LK, Margolis SS, Jensen M, Herman CE, Dunphy WG, Rathmell JC, Kornbluth S (2005) Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2. Cell 123:89–103
Kawahara A, Baker BS, Tata JR (1991) Developmental and regional expression of thyroid hormone receptor genes during Xenopus metamorphosis. Development 112:933–943
Yaoita Y, Brown DD (1990) A correlation of thyroid hormone receptor gene expression with amphibian metamorphosis. Genes Dev 4:1917–1924
Sterling K (1991) Thyroid hormone action: identification of the mitochondrial thyroid hormone receptor as adenine nucleotide translocase. Thyroid 1:167–171
Sterling K, Brenner MA (1995) Thyroid hormone action: effect of triiodothyronine on mitochondrial adenine nucleotide translocase in vivo and in vitro. Metab: Clin Exp 44:193–199
Jouaville LS, Pinton P, Bastianutto C, Rutter GA, Rizzuto R (1999) Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming. Proc Natl Acad Sci USA 96:13807–13812
McCormack JG, Denton RM (1994) Signal transduction by intramitochondrial Ca2+ in mammalian energy metabolism. NIPS 9:71–76
McCormack JG, Halestrap AP, Denton PM (1990) Role of calcium ions regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425
Arnold S, Goglia F, Kadenbach B (1998) 3,5-Diiodothyronine binds to subunit Va of cytochrome-c oxidase and abolishes the allosteric inhibition of respiration by ATP. Eur J Biochem 252:325–330
Lee I, Bender E, Kadenbach B (2002) Control of mitochondrial membrane potential and ROS formation by reversible phosphorylation of cytochrome c oxidase. Mol Cell Biochem 234–235:63–70
Jouaville LS, Ichas F, Holmuhamedov EL, Camacho P, Lechleiter JD (1995) Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature 377:438–441
Bender E, Kadenbach B (2000) The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett 466:130–134
Starkov AA (1997) “Mild” uncoupling of mitochondria. Biosci Rep 17:273–279
Nagasawa T, Suzuki S, Takeda T, DeGroot LJ (1997) Thyroid hormone receptor beta 1 expression in developing mouse limbs and face. Endocrinology 138:1276–1281
Yamano K, Miwa S (1998) Differential gene expression of thyroid hormone receptor alpha and beta in fish development. Gen Comp Endocrinol 109:75–85
Power DM, Llewellyn L, Faustino M, Nowell MA, Bjornsson BT, Einarsdottir IE, Canario AV, Sweeney GE (2001) Thyroid hormones in growth and development of fish. Comp Biochem Physiol C Toxicol Pharmacol 130:447–459
Nowell MA, Power DM, Canario AV, Llewellyn L, Sweeney GE (2001) Characterization of a sea bream (Sparus aurata) thyroid hormone receptor-beta clone expressed during embryonic and larval development. Gen Comp Endocrinol 123:80–89
Oofusa K, Tooi O, Kashiwagi A, Kashiwagi K, Kondo Y, Watanabe Y, Sawada T, Fujikawa K, Yoshizato K (2001) Expression of thyroid hormone receptor betaA gene assayed by transgenic Xenopus laevis carrying its promoter sequences. Mol Cell Endocrinol 181:97–110
Acknowledgements
We wish to thank Erin Manitou and the Electron Microscopy Pathology Core and Victoria Centonze Frohlich and the Imaging Core Facility at UTHSCSA. Financial support: This work was supported by National Institutes of Health Grant R01 GM48451 and PO1 AG19316.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Saelim, N., Holstein, D., Chocron, E.S. et al. Inhibition of apoptotic potency by ligand stimulated thyroid hormone receptors located in mitochondria. Apoptosis 12, 1781–1794 (2007). https://doi.org/10.1007/s10495-007-0109-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-007-0109-1