Semin Reprod Med 2015; 33(03): 185-194
DOI: 10.1055/s-0035-1552583
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Role of a Mitochondrial Progesterone Receptor (PR-M) in Progesterone Action

Thomas M. Price
1   Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
,
Qunsheng Dai
1   Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina
› Author Affiliations
Further Information

Publication History

Publication Date:
02 June 2015 (online)

Abstract

Historically, progesterone functions to regulate gene expression via two nuclear progesterone receptors (PR-B and PR-A). Yet, actions of progesterone independent of gene regulation have been observed for decades. These are based on progesterone induced cellular events that occur too rapidly to involve gene transcription or in cells lacking active gene transcription such as mature spermatozoa. Understanding of these “nongenomic” effects has been slowed by the lack of identification of specific receptors. Previous discovery of a mitochondrial progesterone receptor, PR-M, has opened up the possibility of direct, ligand-dependent modulation of mitochondrial activity. In this article, we review the current knowledge of PR-M and speculate on possible physiologic and pathophysiologic actions.

 
  • References

  • 1 Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev 1997; 18 (4) 502-519
  • 2 Boonyaratanakornkit V, McGowan E, Sherman L, Mancini MA, Cheskis BJ, Edwards DP. The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Mol Endocrinol 2007; 21 (2) 359-375
  • 3 Thomas P, Pang Y, Dong J , et al. Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor α subtypes and their evolutionary origins. Endocrinology 2007; 148 (2) 705-718
  • 4 Falkenstein E, Meyer C, Eisen C, Scriba PC, Wehling M. Full-length cDNA sequence of a progesterone membrane-binding protein from porcine vascular smooth muscle cells. Biochem Biophys Res Commun 1996; 229 (1) 86-89
  • 5 Lessey BA, Alexander PS, Horwitz KB. The subunit structure of human breast cancer progesterone receptors: characterization by chromatography and photoaffinity labeling. Endocrinology 1983; 112 (4) 1267-1274
  • 6 Horwitz KB, Alexander PS. In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation. Endocrinology 1983; 113 (6) 2195-2201
  • 7 Guiochon-Mantel A, Loosfelt H, Lescop P , et al. Mechanisms of nuclear localization of the progesterone receptor: evidence for interaction between monomers. Cell 1989; 57 (7) 1147-1154
  • 8 Tetel MJ, Jung S, Carbajo P, Ladtkow T, Skafar DF, Edwards DP. Hinge and amino-terminal sequences contribute to solution dimerization of human progesterone receptor. Mol Endocrinol 1997; 11 (8) 1114-1128
  • 9 Wardell SE, Boonyaratanakornkit V, Adelman JS, Aronheim A, Edwards DP. Jun dimerization protein 2 functions as a progesterone receptor N-terminal domain coactivator. Mol Cell Biol 2002; 22 (15) 5451-5466
  • 10 Saner KJ, Welter BH, Zhang F , et al. Cloning and expression of a novel, truncated, progesterone receptor. Mol Cell Endocrinol 2003; 200 (1-2) 155-163
  • 11 Kozak M. An analysis of 5′-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res 1987; 15 (20) 8125-8148
  • 12 Rapaport D. Finding the right organelle. Targeting signals in mitochondrial outer-membrane proteins. EMBO Rep 2003; 4 (10) 948-952
  • 13 Gronemeyer H, Meyer ME, Bocquel MT, Kastner P, Turcotte B, Chambon P. Progestin receptors: isoforms and antihormone action. J Steroid Biochem Mol Biol 1991; 40 (1-3) 271-278
  • 14 Wei LL, Gonzalez-Aller C, Wood WM, Miller LA, Horwitz KB. 5′-Heterogeneity in human progesterone receptor transcripts predicts a new amino-terminal truncated “C”-receptor and unique A-receptor messages. Mol Endocrinol 1990; 4 (12) 1833-1840
  • 15 Dai Q, Shah AA, Garde RV , et al. A truncated progesterone receptor (PR-M) localizes to the mitochondrion and controls cellular respiration. Mol Endocrinol 2013; 27 (5) 741-753
  • 16 Wan Y, Coxe KK, Thackray VG, Housley PR, Nordeen SK. Separable features of the ligand-binding domain determine the differential subcellular localization and ligand-binding specificity of glucocorticoid receptor and progesterone receptor. Mol Endocrinol 2001; 15 (1) 17-31
  • 17 Greenawalt JW. The isolation of outer and inner mitochondrial membranes. Methods Enzymol 1974; 31: 310-323
  • 18 Jafri MS, Dudycha SJ, O'Rourke B. Cardiac energy metabolism: models of cellular respiration. Annu Rev Biomed Eng 2001; 3: 57-81
  • 19 Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am J Physiol Cell Physiol 2004; 287 (4) C817-C833
  • 20 Duchen MR. Mitochondria and calcium: from cell signalling to cell death. J Physiol 2000; 529 (Pt 1) 57-68
  • 21 Maldonado EN, Lemasters JJ. ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect. Mitochondrion 2014; 19 (Pt A) 78-84
  • 22 Porcelli AM, Ghelli A, Zanna C, Pinton P, Rizzuto R, Rugolo M. pH difference across the outer mitochondrial membrane measured with a green fluorescent protein mutant. Biochem Biophys Res Commun 2005; 326 (4) 799-804
  • 23 Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V. In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. Biochem J 2004; 377 (Pt 2) 347-355
  • 24 Das S, Wong R, Rajapakse N, Murphy E, Steenbergen C. Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation. Circ Res 2008; 103 (9) 983-991
  • 25 Lee AC, Zizi M, Colombini M. β-NADH decreases the permeability of the mitochondrial outer membrane to ADP by a factor of 6. J Biol Chem 1994; 269 (49) 30974-30980
  • 26 Lemasters JJ, Holmuhamedov EL, Czerny C, Zhong Z, Maldonado EN. Regulation of mitochondrial function by voltage dependent anion channels in ethanol metabolism and the Warburg effect. Biochim Biophys Acta 2012; 1818 (6) 1536-1544
  • 27 Rostovtseva TK, Sheldon KL, Hassanzadeh E , et al. Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci U S A 2008; 105 (48) 18746-18751
  • 28 Behera MA, Dai Q, Garde R, Saner C, Jungheim E, Price TM. Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells. Am J Physiol Endocrinol Metab 2009; 297 (5) E1089-E1096
  • 29 Moran TJ, Gray S, Mikosz CA, Conzen SD. The glucocorticoid receptor mediates a survival signal in human mammary epithelial cells. Cancer Res 2000; 60 (4) 867-872
  • 30 Krämer EA, Seeger H, Krämer B, Wallwiener D, Mueck AO. The effects of progesterone, medroxyprogesterone acetate, and norethisterone on growth factor- and estradiol-treated human cancerous and noncancerous breast cells. Menopause 2005; 12 (4) 468-474
  • 31 Krämer EA, Seeger H, Krämer B, Wallwiener D, Mueck AO. Characterization of the stimulatory effect of medroxyprogesterone acetate and chlormadinone acetate on growth factor treated normal human breast epithelial cells. J Steroid Biochem Mol Biol 2006; 98 (2-3) 174-178
  • 32 Mandal S, Guptan P, Owusu-Ansah E, Banerjee U. Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev Cell 2005; 9 (6) 843-854
  • 33 Harper JA, Dickinson K, Brand MD. Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obes Rev 2001; 2 (4) 255-265
  • 34 Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD. Calcium and mitochondria. FEBS Lett 2004; 567 (1) 96-102
  • 35 Hulbert AJ, Else PL. Mechanisms underlying the cost of living in animals. Annu Rev Physiol 2000; 62: 207-235
  • 36 Gallagher D, Albu J, He Q , et al. Small organs with a high metabolic rate explain lower resting energy expenditure in African American than in white adults. The American Journal of Clinical Nutrition 2006; 83: 1062-1067
  • 37 Buffenstein R, Poppitt SD, McDevitt RM, Prentice AM. Food intake and the menstrual cycle: a retrospective analysis, with implications for appetite research. Physiol Behav 1995; 58 (6) 1067-1077
  • 38 Webb P. 24-hour energy expenditure and the menstrual cycle. Am J Clin Nutr 1986; 44 (5) 614-619
  • 39 Lebenstedt M, Platte P, Pirke KM. Reduced resting metabolic rate in athletes with menstrual disorders. Med Sci Sports Exerc 1999; 31 (9) 1250-1256
  • 40 Kopp-Hoolihan LE, van Loan MD, Wong WW, King JC. Longitudinal assessment of energy balance in well-nourished, pregnant women. Am J Clin Nutr 1999; 69 (4) 697-704
  • 41 Stephenson LA, Kolka MA. Menstrual cycle phase and time of day alter reference signal controlling arm blood flow and sweating. Am J Physiol 1985; 249 (2, Pt 2) R186-R191
  • 42 Stachenfeld NS, Silva C, Keefe DL. Estrogen modifies the temperature effects of progesterone. J Appl Physiol (1985) 2000; 88 (5) 1643-1649
  • 43 Tsai CL, Matsumura K, Nakayama T. Effects of progesterone on thermosensitive neurons in preoptic slice preparations. Neurosci Lett 1988; 86 (1) 56-60
  • 44 Boulant JA. Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin Infect Dis 2000; 31 (Suppl 5) S157-S161
  • 45 Charkoudian N, Stachenfeld NS. Reproductive hormone influences on thermoregulation in women. Compr Physiol 2014; 4 (2) 793-804
  • 46 Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 2011; 301 (5) R1207-R1228
  • 47 Ushikubi F, Segi E, Sugimoto Y , et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998; 395 (6699) 281-284
  • 48 Silva NL, Boulant JA. Effects of testosterone, estradiol, and temperature on neurons in preoptic tissue slices. Am J Physiol 1986; 250 (4, Pt 2) R625-R632
  • 49 Charkoudian N, Johnson JM. Altered reflex control of cutaneous circulation by female sex steroids is independent of prostaglandins. Am J Physiol 1999; 276 (5, Pt 2) H1634-H1640
  • 50 Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 2010; 151 (8) 3479-3489
  • 51 Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, McMullen NT, Rance NE. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci U S A 2012; 109 (48) 19846-19851
  • 52 Valente A, Jamurtas AZ, Koutedakis Y, Flouris AD. Molecular pathways linking non-shivering thermogenesis and obesity: focusing on brown adipose tissue development. Biol Rev Camb Philos Soc 2015; 90 (1) 77-88
  • 53 Cypess AM, Lehman S, Williams G , et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360 (15) 1509-1517
  • 54 Santos GM, Neves FA, Amato AA. Thermogenesis in white adipose tissue: an unfinished story about PPARγ. Biochim Biophys Acta 2015; 1850 (4) 691-695
  • 55 Lee P, Swarbrick MM, Ho KKY. Brown adipose tissue in adult humans: a metabolic renaissance. Endocr Rev 2013; 34 (3) 413-438
  • 56 Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging 2002; 29 (10) 1393-1398
  • 57 Seale P, Kajimura S, Yang W , et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007; 6 (1) 38-54
  • 58 Virtanen KA, Lidell ME, Orava J , et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360 (15) 1518-1525
  • 59 Cerri M, Morrison SF. Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis. Neuroscience 2005; 135 (2) 627-638
  • 60 Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab 2012; 15 (4) 480-491
  • 61 Lowell BB, S-Susulic V, Hamann A , et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993; 366 (6457) 740-742
  • 62 Saito M, Okamatsu-Ogura Y, Matsushita M , et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009; 58 (7) 1526-1531
  • 63 Rodriguez-Cuenca S, Monjo M, Frontera M, Gianotti M, Proenza AM, Roca P. Sex steroid receptor expression profile in brown adipose tissue. Effects of hormonal status. Cell Physiol Biochem 2007; 20 (6) 877-886
  • 64 Monjo M, Rodríguez AM, Palou A, Roca P. Direct effects of testosterone, 17 β-estradiol, and progesterone on adrenergic regulation in cultured brown adipocytes: potential mechanism for gender-dependent thermogenesis. Endocrinology 2003; 144 (11) 4923-4930
  • 65 Rodríguez-Cuenca S, Monjo M, Gianotti M, Proenza AM, Roca P. Expression of mitochondrial biogenesis-signaling factors in brown adipocytes is influenced specifically by 17beta-estradiol, testosterone, and progesterone. Am J Physiol Endocrinol Metab 2007; 292 (1) E340-E346
  • 66 Rodríguez AM, Monjo M, Roca P, Palou A. Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes. Cell Mol Life Sci 2002; 59 (10) 1714-1723
  • 67 Smith WS, Broadbridge R, East JM, Lee AG. Sarcolipin uncouples hydrolysis of ATP from accumulation of Ca2+ by the Ca2+-ATPase of skeletal-muscle sarcoplasmic reticulum. Biochem J 2002; 361 (Pt 2) 277-286
  • 68 Bal NC, Maurya SK, Sopariwala DH , et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 2012; 18 (10) 1575-1579
  • 69 Bombardier E, Smith IC, Gamu D , et al. Sarcolipin trumps β-adrenergic receptor signaling as the favored mechanism for muscle-based diet-induced thermogenesis. FASEB J 2013; 27 (9) 3871-3878
  • 70 Feng Q, Crochet JR, Dai Q, Leppert PC, Price TM. Expression of a mitochondrial progesterone receptor (PR-M) in leiomyomata and association with increased mitochondrial membrane potential. J Clin Endocrinol Metab 2014; 99 (3) E390-E399
  • 71 Tantibhedhyangkul J, Hawkins KC, Dai Q , et al. Expression of a mitochondrial progesterone receptor in human spermatozoa correlates with a progestin-dependent increase in mitochondrial membrane potential. Andrology 2014; 2 (6) 875-883
  • 72 Teves ME, Barbano F, Guidobaldi HA, Sanchez R, Miska W, Giojalas LC. Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa. Fertil Steril 2006; 86 (3) 745-749
  • 73 Baldi E, Luconi M, Muratori M, Marchiani S, Tamburrino L, Forti G. Nongenomic activation of spermatozoa by steroid hormones: facts and fictions. Mol Cell Endocrinol 2009; 308 (1-2) 39-46
  • 74 Contreras HR, Llanos MN. Detection of progesterone receptors in human spermatozoa and their correlation with morphological and functional properties. Int J Androl 2001; 24 (4) 246-252
  • 75 Kirkman-Brown JC, Punt EL, Barratt CL, Publicover SJ. Zona pellucida and progesterone-induced Ca2+ signaling and acrosome reaction in human spermatozoa. J Androl 2002; 23 (3) 306-315
  • 76 Sachdeva G, Shah CA, Kholkute SD, Puri CP. Detection of progesterone receptor transcript in human spermatozoa. Biol Reprod 2000; 62 (6) 1610-1614
  • 77 Luconi M, Bonaccorsi L, Bini L , et al. Characterization of membrane nongenomic receptors for progesterone in human spermatozoa. Steroids 2002; 67 (6) 505-509
  • 78 Strünker T, Goodwin N, Brenker C , et al. The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 2011; 471 (7338) 382-386
  • 79 Amaral A, Lourenço B, Marques M, Ramalho-Santos J. Mitochondria functionality and sperm quality. Reproduction 2013; 146 (5) R163-R174
  • 80 Shynlova O, Tsui P, Jaffer S, Lye SJ. Integration of endocrine and mechanical signals in the regulation of myometrial functions during pregnancy and labour. Eur J Obstet Gynecol Reprod Biol 2009; 144 (Suppl 1) S2-S10
  • 81 Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS. Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab 1993; 76 (2) 513-517
  • 82 Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005; 26 (3) 423-438
  • 83 Maruo T, Matsuo H, Samoto T , et al. Effects of progesterone on uterine leiomyoma growth and apoptosis. Steroids 2000; 65 (10-11) 585-592
  • 84 Ferenczy A, Richart RM, Okagaki T. A comparative ultrastructural study of leiomyosarcoma, cellular leiomyoma, and leiomyoma of the uterus. Cancer 1971; 28 (4) 1004-1018