Semin Reprod Med 2007; 25(3): 154-164
DOI: 10.1055/s-2007-973428
Copyright © 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Actions of Steroids in Mitochondria

Larisa P. Gavrilova-Jordan1 , Thomas M. Price1
  • 1Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
Further Information

Publication History

Publication Date:
20 April 2007 (online)

ABSTRACT

Investigations of indirect and direct actions of steroids on the mitochondria are relatively new areas of research. In this review we provide brief background information regarding mitochondrial structure and function and then focus upon interactions of glucocorticoid, estrogen, androgen, and progesterone receptors with mitochondria. We evaluate the current evidence for steroid receptor localization in the mitochondria based on techniques of Western blot analysis, immunocytochemistry, electron microscopy, and mass spectrometry. Steroid receptor-dependent interactions with mitochondria may include transcriptional regulation of nuclear DNA-encoded mitochondrial proteins, transcriptional regulation of mitochondrial DNA-encoded proteins, or indirect effects on mitochondria due to interactions with cytoplasmic signaling peptides and non-genomic control of cation fluxes. These interactions may play a role in mitochondrial-dependent processes of oxidative phosphorylation and apoptosis. Physiological examples of these interactions are discussed.

REFERENCES

  • 1 Logan D C. The mitochondrial compartment.  J Exp Bot. 2006;  57 1225-1243
  • 2 Mannella C A. Structure and dynamics of the mitochondrial inner membrane cristae.  Biochim Biophys Acta. 2006;  1763 542-548
  • 3 Mannella C A. The relevance of mitochondrial membrane topology to mitochondrial function.  Biochim Biophys Acta. 2006;  1762 140-147
  • 4 Alberts B. Energy conversion: mitochondria and chloroplasts. In: Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P Molecular Biology of the Cell. New York; Garland Science 2002
  • 5 Chen H, Chan D. Emerging functions of mammalian mitochondrial fusion and fission.  Hum Mol Genet. 2005;  14 R283-R289
  • 6 Montoya J, Ojala D, Attardi G. Distinctive features of the 5′-terminal sequences of the human mitochondrial mRNAs.  Nature. 1981;  290 465-470
  • 7 Johnson D T, Harris R A, Blair P V, Balaban R S. Functional consequences of mitochondrial proteome heterogeneity.  Am J Physiol Cell Physiol. 2006; September 13 ;  , (Epub ahead of print)
  • 8 Anderson S, Bankier A T, Barrell B G et al.. Sequence and organization of the human mitochondrial genome.  Nature. 1981;  290 457-465
  • 9 Goffart S, Wiesner R J. Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis.  Exp Physiol. 2003;  88 33-40
  • 10 Jafri M S, Dudycha S J, O'Rourke B. Cardiac energy metabolism: models of cellular respiration.  Annu Rev Biomed Eng. 2001;  3 57-81
  • 11 Energy conversion: the formation of ATP in mitochondria and bacteria. In: Darnel J, Lodish H, Baltimore D Molecular Cell Biology. New York; WH Freeman 1990
  • 12 Gilkerson R W, Selker J M, Capaldi R A. The cristal membrane of mitochondria is the principal site of oxidative phosphorylation.  FEBS Lett. 2003;  546 355-358
  • 13 Brookes P S, Yoon Y, Robotham J L, Anders M W, Sheu S S. Calcium, ATP, and ROS: a mitochondrial love-hate triangle.  Am J Physiol Cell Physiol. 2004;  287 C817-C833
  • 14 Duchen M R. Mitochondria and calcium: from cell signalling to cell death.  J Physiol. 2000;  529(1) 57-68
  • 15 Gunter T E, Yule D I, Gunter K K, Eliseev R A, Salter J D. Calcium and mitochondria.  FEBS Lett. 2004;  567 96-102
  • 16 Kirichok Y, Krapivinsky G, Clapham D. The mitochondrial calcium uniporter is a highly selective ion channel.  Nature. 2004;  427 360-364
  • 17 Hulbert A, Else P. Mechanisms underlying the cost of living in animals.  Annu Rev Physiol. 2000;  62 207-235
  • 18 Harper J A, Dickinson K, Brand M D. Mitochondrial uncoupling as a target for drug development for the treatment of obesity.  Obes Rev. 2001;  2 255-265
  • 19 Gustafsson A, Gottlieb R. Bcl-2 family members and apoptosis, taken to heart.  Am J Physiol Cell Physiol. 2007;  292 C45-C51
  • 20 Kaufmann S H, Gores G J. Apoptosis in cancer: cause and cure.  Bioessays. 2000;  22 1007-1017
  • 21 Kam P CA, Ferch N I. Apoptosis: mechanisms and clinical implications.  Anaesthesia. 2000;  55 1081-1093
  • 22 Khosravi-Far R, Esposti M. Death receptor signals to mitochondria.  Cancer Biol Ther. 2004;  3 1051-1057
  • 23 Chowdhury I, Tharakan B, Bhat G. Current concepts in apoptosis: the physiological suicide program revisited.  Cell Mol Biol Lett. 2006;  11 506-525
  • 24 Cho S G, Choi E J. Apoptotic signaling pathways: caspases and stress-activated protein kinases.  J Biochem Mol Biol. 2002;  35 24-27
  • 25 Er E, Oliver L, Cartron P, Juin P, Manon S, Vallette F. Mitochondria as the target of the pro-apoptotic protein bax.  Biochim Biophys Acta. 2006;  1757 1301-1311
  • 26 Kim R, Emi M, Tanabe K. Caspase-dependent and-independent cell death pathways after DNA damage.  Oncol Rep. 2005;  14 595-599
  • 27 Skommer J, Wlodkowic D, Deptala A. Mitochondria and the bcl-2 family.  Leuk Res. 2007;  31 277-286
  • 28 Samraj A K, Keil E, Ueffing N, Schulze-Osthoff K, Schmitz I. Loss of caspase-9 provides genetic evidence for the type i/ii concept of cd95-mediated apoptosis.  J Biol Chem. 2006;  281 29652-29659
  • 29 Preston T J, Abadi A, Wilson L, Singh G. Mitochondrial contributions to cancer cell physiology: potential for drug development.  Adv Drug Deliv Rev. 2001;  49 45-61
  • 30 Green D R. Apoptotic pathways: ten minutes to dead.  Cell. 2005;  121 671-674
  • 31 Siskind L J. Mitochondrial ceramide and the induction of apoptosis.  J Bioenerg Biomembr. 2005;  37 143-153
  • 32 Danial N N, Korsmeyer S J. Cell death: critical control points.  Cell. 2004;  116 205-219
  • 33 Green D R, Kroemer G. The pathophysiology of mitochondrial cell death.  Science. 2004;  305 626-629
  • 34 Halestrap A P. Calcium, mitochondria and reperfusion injury: a pore way to die.  Biochem Soc Trans. 2006;  34 232-237
  • 35 Jegathesan J, Liebenthal J, Arnett M, Clancy R, Pierce J. Apoptosis: understanding the new molecular pathway.  Medsurg Nurs. 2004;  13 371-375
  • 36 Demonacos C, Tsawdaroglou N C, Djordjevic-Markovic R et al.. Import of the glucocorticoid receptor into rat liver mitochondria in vivo and in vitro.  J Steroid Biochem Mol Biol. 1993;  46 401-413
  • 37 Psarra A M, Solakidi S, Trougakos I P, Margaritis L H, Spyrou G, Sekeris C E. Glucocorticoid receptor isoforms in human hepatocarcinoma HepG2 and SaOS-2 osteosarcoma cells: presence of glucocorticoid receptor alpha in mitochondria and of glucocorticoid receptor beta in nucleoli.  Int J Biochem Cell Biol. 2005;  37 2544-2558
  • 38 Koufali M M, Moutsatsou P, Sekeris C E, Breen K C. The dynamic localization of the glucocorticoid receptor in rat C6 glioma cell mitochondria.  Mol Cell Endocrinol. 2003;  209 51-60
  • 39 Moutsatsou P, Psarra A M, Tsiapara A, Paraskevakou H, Davaris P, Sekeris C E. Localization of the glucocorticoid receptor in rat brain mitochondria.  Arch Biochem Biophys. 2001;  386 69-78
  • 40 Sionov R V, Cohen O, Kfir S, Zilberman Y, Yefenof E. Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis.  J Exp Med. 2006;  203 189-201
  • 41 Chen F, Watson C, Gametchu B. Association of the glucocorticoid receptor alternatively-spliced transcript 1A with the presence of the high molecular weight membrane glucocorticoid receptor in mouse lymphoma cells.  J Cell Biochem. 1999;  74 430-446
  • 42 Sionov R V, Cohen O, Kfir S, Zilberman Y, Yefenof E. Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis.  J Exp Med. 2006;  203 189-201
  • 43 Sionov R V, Kfir S, Zafrir E, Cohen O, Zilberman Y, Yefenof E. Glucocorticoid-induced apoptosis revisited: a novel role for glucocorticoid receptor translocation to the mitochondria.  Cell Cycle. 2006;  5 1017-1026
  • 44 Grossman A, Oppenheim J, Grondin G, St. Jean P, Beaudoin A. Immunocytochemical localization of the [3h]estradiol-binding protein in rat pancreatic acinar cells.  Endocrinology. 1989;  124 2857-2866
  • 45 Noteboom W D, Gorski J. Stereo specific binding of estrogens in the rat uterus.  Arch Biochem Biophys. 1965;  111 559-568
  • 46 Moats I IRK, Ramirez V D. Rapid uptake and binding of estradiol-17beta-6-(o-carboxymethyl)oxime:125i-labeled BSA by female rat liver.  Biol Reprod. 1998;  58 531-538
  • 47 Monje P, Boland R. Subcellular distribution of native estrogen receptor alpha and beta isoforms in rabbit uterus and ovary.  J Cell Biochem. 2001;  82 467-479
  • 48 Chen J Q, Delannoy M, Cooke C, Yager J D. Mitochondrial localization of ERα and ERβ in human MCF7 cells.  Am J Physiol Endocrinol Metab. 2004;  286 E1011-E1022
  • 49 Cammarata P R, Chu S, Moor A, Wang Z, Yang S H, Simpkins J W. Subcellular distribution of native estrogen receptor alpha and beta subtypes in cultured human lens epithelial cells.  Exp Eye Res. 2004;  78 861-871
  • 50 Yang S-H, Liu R, Perez E J et al.. Mitochondrial localization of estrogen receptor β.  Proc Natl Acad Sci USA. 2004;  101 4130-4135
  • 51 Schwend T, Gustafsson J-A. False positives in MALDI-TOF detection of ERB in mitochondria.  Biochem Biophys Res Commun. 2006;  343 707-711
  • 52 Yang S-H, Prokai L, Simpkins J W. Correspondence regarding Schwend and Gustafsson, “False positives in MALDI-TOF detection of ER[beta] in mitochondria.  Biochem Biophys Res Commun. 2006;  345 917-918
  • 53 Rapaport D. Targeting signals in mitochondrial outer-membrane proteins.  EMBO Rep. 2003;  4 948-952
  • 54 Emanuelsson O, Nielsen H, Brunak S, Von Heijne G. Predicting subcellular localization of proteins based on their N-terminal amino acid sequence.  J Mol Biol. 2000;  300 1005-1016
  • 55 Chen J, Delannoy M, Cooke C, Yager J. Mitochondrial localization of ERα and ERβ in human MCF-7 cells.  Am J Physiol Endocrinol Metab. 2004;  286 1011-1022
  • 56 Solakidi S, Psarra A MG, Nikolaropoulos S, Sekeris C E. Estrogen receptors α and β (ERα and ERβ) and androgen receptor (AR) in human sperm: localization of ER{beta} and AR in mitochondria of the midpiece.  Hum Reprod. 2005;  20 3481-3487
  • 57 Saner K J, Welter B H, Zhang F et al.. Cloning and expression of a novel, truncated progesterone receptor.  Mol Cell Endocrinol. 2003;  200 155-163
  • 58 Scheller K, Sekeris C E. The effects of steroid hormones on the transcription of genes encoding enzymes of oxidative phosphorylation.  Exp Physiol. 2003;  88 129-140
  • 59 Weber K, Bruck P, Mikes Z, Kupper J-H, Klingenspor M, Wiesner R J. Glucocorticoid hormone stimulates mitochondrial biogenesis specifically in skeletal muscle.  Endocrinology. 2002;  143 177-184
  • 60 Del Arco A, Satrustegui J. Identification of a novel human subfamily of mitochondrial carriers with calcium-binding domains.  J Biol Chem. 2004;  279 24701-24713
  • 61 Tsiriyotis C, Spandidos D A, Sekeris C E. The mitochondrion as a primary site of action of glucocorticoids: mitochondrial nucleotide sequences, showing similarity to hormone response elements, confer dexamethasone inducibility to chimaeric genes transfected in LATK- cells.  Biochem Biophys Res Commun. 1997;  235 349-354
  • 62 Ioannou I M, Tsawdaroglou N, Sekeris C E. Presence of glucocorticoid responsive elements in the mitochondrial genome.  Anticancer Res. 1988;  8 1405-1409
  • 63 Demonacos C, Djordjevic-Markovic R, Tsawdaroglou N, Sekeris C E. The mitochondrion as a primary site of action of glucocorticoids: the interaction of the glucocorticoid receptor with mitochondrial DNA sequences showing partial similarity to the nuclear glucocorticoid responsive elements.  J Steroid Biochem Mol Biol. 1995;  55 43-55
  • 64 Kadowaki T, Kitawaga Y. Enhanced transcription of mitochondrial genes after growth stimulation and glucocorticoid treatment of Reuber hepatoma H35 cells.  FEBS Lett. 1988;  233 51-86
  • 65 Van Itallie C M. Dexamethasone treatment increases mitochondrial RNA synthesis in a rat hepatoma cell line.  Endocrinology. 1992;  130 567-576
  • 66 Song I-H, Buttgereit F. Non-genomic glucocorticoid effects to provide the basis for new drug developments.  Mol Cell Endocrinol. 2006;  246 142-146
  • 67 Watanabe T, Inoue S, Hiroi H, Orimo A, Kawashima H, Muramatsu M. Isolation of estrogen-responsive genes with a CpG island library.  Mol Cell Biol. 1998;  18 442-449
  • 68 Weisz A, Basile W, Scafoglio C et al.. Molecular identification of ERalpha-positive breast cancer cells by the expression profile of an intrinsic set of estrogen regulated genes.  J Cell Physiol. 2004;  200 440-450
  • 69 Stirone C, Duckles S, Krause D, Procaccio V. Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels.  Mol Pharmacol. 2005;  68 959-965
  • 70 Van Itallie C M, Dannies P. Estrogen induces accumulation of the mitochondrial ribonucleic acid for subunit ii of cytochrome oxidase in pituitary tumor cells.  Mol Endocrinol. 1988;  2 332-337
  • 71 Chen J Q, Delannoy M, Cooke C, Yager J D. Mitochondrial localization of ERα and ERβ in human MCF7 cells.  Am J Physiol Endocrinol Metab. 2004;  286 E1011-E1022
  • 72 Bettini E, Maggi A. Estrogen induction of cytochrome c oxidase subunit iii in rat hippocampus.  J Neurochem. 1992;  58 1923-1929
  • 73 Psarra A M, Solakidi S, Sekeris C E. The mitochondrion as a primary site of action of steroid and thyroid hormones: presence and action of steroid and thyroid hormone receptors in mitochondria of animal cells.  Mol Cell Endocrinol. 2006;  246 21-33
  • 74 Chen J Q, Eshete M, Alworth W L, Yager J D. Binding of MCF-7 cell mitochondrial proteins and recombinant human estrogen receptors alpha and beta to human mitochondrial DNA estrogen response elements.  J Cell Biochem. 2004;  93 358-373
  • 75 Bryant D N, Sheldahl L C, Marriott L K, Shapiro R A, Dorsa D M. Multiple pathways transmit neuroprotective effects of gonadal steroids.  Endocrine. 2006;  29 199-207
  • 76 Kirkland R A, Franklin J L. BAX, reactive oxygen, and cytochrome c release in neuronal apoptosis.  Antioxid Redox Signal. 2003;  5 589-596
  • 77 Lobaton C D, Vay L, Hernandez-Sanmiguel E et al.. Modulation of mitochondrial Ca2 + uptake by estrogen receptor agonists and antagonists.  Br J Pharmacol. 2005;  145 862-871
  • 78 Parkash J, Felty Q, Roy D. Estrogen exerts a spatial and temporal influence on reactive oxygen species generation that precedes calcium uptake in high-capacity mitochondria: implications for rapid nongenomic signaling of cell growth.  Biochemistry. 2006;  45 2872-2881
  • 79 Juang H H, Hseih M L, Tsui K H. Testosterone modulates mitochondrial aconitase in the full-length human androgen receptor-transfected PC-3 prostatic carcinoma cells.  J Mol Endocrinol. 2004;  33 121-132
  • 80 Beauchemin A MJ, Gottlieb B, Beitel L K, Elhaji Y A, Pinsky L, Trifiro M A. Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy.  Brain Res Bull. 2001;  56 285-297
  • 81 Lin Y, Kokontis J, Tang F et al.. Androgen and its receptor promote Bax-mediated apoptosis.  Mol Cell Biol. 2006;  26 1908-1916
  • 82 Er F, Michels G, Gassanov N, Rivero F, Hoppe U C. Testosterone induces cytoprotection by activating ATP-sensitive K + channels in the cardiac mitochondrial inner membrane.  Circulation. 2004;  110 3100-3107
  • 83 Brillion D J, Zheng B, Cambell R G, Matthews D E. Effect of cortisol on energy expenditure and amino acid metabolism in humans.  Am J Physiol. 1995;  268 E501-E513
  • 84 Weber K, Bruck P, Mikes Z, Kupper J H, Klingenspor M, Wiesner R J. Glucocorticoid hormone stimulates mitochondrial biogenesis specifically in skeletal muscle.  Endocrinology. 2002;  143 177-184
  • 85 Distelhorst C W. Recent insights into the mechanisms of glucocorticosteroid-induced apoptosis.  Cell Death Differ. 2002;  9 6-19
  • 86 Buffenstein R, Poppitt S D, Mcdevitt R M, Prentice A M. Food intake and the menstrual cycle: a retrospective analysis, with implications for appetite research.  Physiol Behav. 1995;  58 1067-1077
  • 87 Webb P. Twenty-four hour energy expenditure and the menstrual cycle.  Am J Clin Nutr. 1986;  44 614-619
  • 88 Lebenstedt M, Petra P, Karl-Martin P. Reduced metabolic rate in athletes with menstrual disorders.  Med Sci Sports Exerc. 1999;  31 1250-1256
  • 89 Koop-Hoolihan L E, Van Loan D, Wong W W, King J C. Longitudinal assessment of energy balance in well-nourished, pregnant women.  Am J Clin Nutr. 1999;  69 697-704
  • 90 Zhai P, Eurell T E, Cooke P S, Lubahn D B, Gross D R. Myocardial ischemia-reperfusion injury in estrogen receptor-alpha knockout and wild-type mice.  Am J Physiol Heart Circ Physiol. 2000;  278 H1640-H1647
  • 91 Zhai P, Eurell T E, Cotthaus R, Jeffery E H, Bahr J M, Gross D R. Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats.  Am J Physiol Heart Circ Physiol. 2000;  279 H2766-H2775
  • 92 Arieli Y, Gursahani H, Eaton M, Hernandez L, Schaefer S. Gender modulation of Ca2 + uptake in cardiac mitochondria.  J Mol Cell Cardiol. 2004;  37 507-513
  • 93 Toda K, Takeda K, Okada T et al.. Targeted disruption of the aromatase P450 gene (Cyp19) in mice and their ovarian and uterine responses to 17beta-oestradiol.  J Endocrinol. 2001;  170 99-111
  • 94 Burris T P, Krishnan V. Estrogen: a mitochondrial energizer that keeps going.  Mol Pharmacol. 2005;  68 956-958
  • 95 Lewis J S, Meeke K, Osipo C et al.. Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation.  J Natl Cancer Inst. 2005;  97 1746-1759
  • 96 Beauchemin A MJ, Gottlieb B, Beitel L K, Elhaji Y A, Pinsky L, Trifiro M A. Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy.  Brain Res Bull. 2001;  56 285-297
  • 97 Zhang H, Zhu Z, Liu L et al.. Upregulation of Fas and FasL expression in testosterone-induced apoptosis of macrophages.  Methods Find Exp Clin Pharmacol. 2003;  25 779-784
  • 98 Verzola D, Gandolfo M T, Salvatore F et al.. Testosterone promotes apoptotic damage in human renal tubular cells.  Kidney Int. 2004;  65 1252-1261
  • 99 Koenig H, Goldstone A, Lu C Y. Androgens regulate mitochondrial cytochrome c oxidase and lysosomal hydrolases in mouse skeletal muscle.  Biochem J. 1980;  192 349-353
  • 100 Wiren K M, Toombs A R, Semirale A A, Zhang X. Osteoblast and osteocyte apoptosis associated with androgen action in bone: requirement of increased Bax/Bcl-2 ratio.  Bone. 2006;  38 637-651
  • 101 Kimura K, Markowski M, Bowen C, Gelmann E P. Androgen blocks apoptosis of hormone-dependent prostate cancer cells.  Cancer Res. 2001;  61 5611-5618
  • 102 Gigli I, Bussmann L E. Exercise and ovarian steroid hormones: their effects on mitochondrial respiration.  Life Sci. 2001;  68 1505-1514
  • 103 Robertson C L, Puskar A, Hoffman G E, Murphy A Z, Saraswati M, Fiskum G. Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss after traumatic brain injury in female rats.  Exp Neurol. 2006;  197 235-243
  • 104 Kosel S, Hofhaus G, Maassen A, Vieregge P, Graeber M. Role of mitochondria in Parkinson disease.  Biol Chem. 1999;  380 865-870
  • 105 Saunders-Pullman R. Estrogens and Parkinson disease: neuroprotective, symptomatic, neither or both?.  Endocrine. 2003;  21 81-87

Thomas M PriceM.D. 

5704 Fayetteville Rd., Durham, NC 27713

Email: price067@mc.duke.edu