Advertisement

Pflügers Archiv - European Journal of Physiology

, Volume 470, Issue 8, pp 1141–1148 | Cite as

Mitochondrial cAMP and Ca2+ metabolism in adrenocortical cells

Invited Review
  • 61 Downloads

Abstract

The biological effects of physiological stimuli of adrenocortical glomerulosa cells are predominantly mediated by the Ca2+ and the cAMP signal transduction pathways. The complex interplay between these signalling systems fine-tunes aldosterone secretion. In addition to the well-known cytosolic interactions, a novel intramitochondrial Ca2+–cAMP interplay has been recently recognised. The cytosolic Ca2+ signal is rapidly transferred into the mitochondrial matrix where it activates Ca2+-sensitive dehydrogenases, thus enhancing the formation of NADPH, a cofactor of steroid synthesis. Quite a few cell types, including H295R adrenocortical cells, express the soluble adenylyl cyclase within the mitochondria and the elevation of mitochondrial [Ca2+] activates the enzyme, thus resulting in the Ca2+-dependent formation of cAMP within the mitochondrial matrix. On the other hand, mitochondrial cAMP (mt-cAMP) potentiates the transfer of cytosolic Ca2+ into the mitochondrial matrix. This cAMP-mediated positive feedback control of mitochondrial Ca2+ uptake may facilitate the rapid hormonal response to emergency situations since knockdown of soluble adenylyl cyclase attenuates aldosterone production whereas overexpression of the enzyme facilitates steroidogenesis in vitro. Moreover, the mitochondrial Ca2+–mt-cAMP–Ca2+ uptake feedback loop is not a unique feature of adrenocortical cells; a similar signalling system has been described in HeLa cells as well.

Keywords

cAMP Ca2+ signal Mitochondria Aldosterone Soluble adenylyl cyclase Adrenocortical cells 

Notes

Acknowledgements

We thank Dr. G. Di Benedetto, Dr. D. Katona, Prof. T. Pozzan, Ms. A. Rajki and Dr. É. Wisniewski for their contribution to the experimental work presented in this review. The discussions with Professors Erzsébet Ligeti and László Tretter and Miklós Geiszt are also appreciated.

Funding information

The study received financial support from the Hungarian National Science Foundation (OTKA NK100883, 108382 and K116954), the János Bólyai Research Scholarship of the Hungarian Academy of Sciences to G.S. and the National Research, Development and Innovation Office (NKFI-6/FK_124038 to G.S.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Spät A, Hunyady L (2004) Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev 84:489–539CrossRefPubMedGoogle Scholar
  2. 2.
    Spät A, Pitter JG (2004) The effect of cytoplasmic Ca2+ signal on the redox state of mitochondrial pyridine nucleotides. Mol Cell Endocrinol 215:115–118CrossRefPubMedGoogle Scholar
  3. 3.
    Spät A, Hunyady L, Szanda G (2016) Signaling interactions in the adrenal cortex. Front Endocrinol (Lausanne) 7:17.  https://doi.org/10.3389/fendo.2016.00017 Google Scholar
  4. 4.
    Bollag WB (2014) Regulation of aldosterone synthesis and secretion. Compr Physiol 4:1017–1055.  https://doi.org/10.1002/cphy.c130037 CrossRefPubMedGoogle Scholar
  5. 5.
    Hyatt PJ, Tait JF, Tait SAS (1986) The mechanism of the effect of K+ on the steroidogenesis of rat zona glomerulosa cells of the adrenal cortex: role of cyclic AMP. Proc R Soc Lond [Biol] 227:21–42CrossRefGoogle Scholar
  6. 6.
    Katona D, Rajki A, Di BG PT, Spät A (2015) Calcium-dependent mitochondrial cAMP production enhances aldosterone secretion. Mol Cell Endocrinol 412:196–204.  https://doi.org/10.1016/j.mce.2015.05.002 CrossRefPubMedGoogle Scholar
  7. 7.
    Tremblay E, Payet MD, Gallo-Payet N (1991) Effects of ACTH and angiotensin II on cytosolic calcium in cultured adrenal glomerulosa cells. Role of cAMP production in the ACTH effect. Cell Calcium 12:655–673CrossRefPubMedGoogle Scholar
  8. 8.
    Willoughby D, Cooper DM (2007) Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev 87:965–1010.  https://doi.org/10.1152/physrev.00049.2006 CrossRefPubMedGoogle Scholar
  9. 9.
    Fagan KA, Graf RA, Tolman S, Schaack J, Cooper DM (2000) Regulation of a Ca2+-sensitive adenylyl cyclase in an excitable cell. Role of voltage-gated versus capacitative Ca2+ entry. J Biol Chem 275:40187–40194.  https://doi.org/10.1074/jbc.M006606200 CrossRefPubMedGoogle Scholar
  10. 10.
    Gallo-Payet N, Grazzini E, Coté M, Chouinard L, Chorvatova A, Bilodeau L, Payet MD, Guillon G (1996) Role of Ca2+ in the action of adrenocorticotropin in cultured human adrenal glomerulosa cells. J Clin Investig 98:460–466CrossRefPubMedGoogle Scholar
  11. 11.
    Durroux T, Gallo-Payet N, Payet MD (1991) Effects of adrenocorticotropin on action potential and calcium currents in cultured rat and bovine glomerulosa cells. Endocrinology 129:2139–2147CrossRefPubMedGoogle Scholar
  12. 12.
    Burgess GM, Bird GSJ, Obie JF, Putney JW Jr (1991) The mechanism for synergism between phospholipase C- and adenylyl cyclase-linked hormones in liver. Cyclic AMP-dependent kinase augments inositol trisphosphate-mediated Ca2+ mobilization without increasing the cellular levels of inositol polyphosphates. J Biol Chem 266:4772–4781PubMedGoogle Scholar
  13. 13.
    Hajnóczky G, Gao E, Nomura T, Hoek JB, Thomas AP (1993) Multiple mechanisms by which protein kinase A potentiates inositol 1,4,5-trisphosphate-induced Ca2+ mobilization in permeabilized hepatocytes. Biochem J 293:413–422CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Enyedi P, Szabadkai G, Horváth A, Szilágyi, Gráf L, Spät A (1994) Inositol 1,4,5-trisphosphate receptor subtypes in adrenal glomerulosa cells. Endocrinology 134:2354–2359CrossRefPubMedGoogle Scholar
  15. 15.
    Balla T, Enyedi P, Hunyady L, Spät A (1984) Effects of lithium on angiotensin-stimulated phosphatidylinositol turnover and aldosterone production in adrenal glomerulosa cells: a possible causal relationship. FEBS Lett 171:179–182CrossRefPubMedGoogle Scholar
  16. 16.
    Hattangady NG, Olala LO, Bollag WB, Rainey WE (2012) Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 350:151–162.  https://doi.org/10.1016/j.mce.2011.07.034 CrossRefPubMedGoogle Scholar
  17. 17.
    Pralong WF, Hunyady L, Várnai P, Wollheim CB, Spät A (1992) Pyridine nucleotide redox state parallels production of aldosterone in potassium-stimulated adrenal glomerulosa cells. Proc Natl Acad Sci U S A 89:132–136CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Duchen MR (1992) Ca2+-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem J 283:41–50CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pralong WF, Spät A, Wollheim CB (1994) Dynamic pacing of cell metabolism by intracellular Ca2+. J Biol Chem 269:27310–27314PubMedGoogle Scholar
  20. 20.
    Hajnóczky G, Robb-Gaspers LD, Seitz MB, Thomas AP (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82:415–424CrossRefPubMedGoogle Scholar
  21. 21.
    Rizzuto R, Simpson AWM, Brini M, Pozzan T (1992) Rapid changes of mitochondrial Ca2+ revealed by specifically targeted recombinant aequorin. Nature 358:325–327CrossRefPubMedGoogle Scholar
  22. 22.
    McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425CrossRefPubMedGoogle Scholar
  23. 23.
    Wiederkehr A, Szanda G, Akhmedov D, Mataki C, Heizmann CW, Schoonjans K, Pozzan T, Spät A, Wollheim CB (2011) Mitochondrial matrix calcium is an activating signal for hormone secretion. Cell Metab 13:601–611CrossRefPubMedGoogle Scholar
  24. 24.
    Spät A, Fülöp L, Szanda G (2012) The role of mitochondrial Ca2+ and NAD(P)H in the control of aldosterone secretion. Cell Calcium 52:64–72.  https://doi.org/10.1016/j.ceca.2012.01.009 CrossRefPubMedGoogle Scholar
  25. 25.
    Jefferson LS, Exton JH, Butcher RW, Sutherland EW, Park CR (1968) Role of adenosine 3′,5′-monophosphate in the effects of insulin and anti-insulin serum on liver metabolism. J Biol Chem 243:1031–1038PubMedGoogle Scholar
  26. 26.
    Buxton IL, Brunton LL (1983) Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes. J Biol Chem 258:10233–10239PubMedGoogle Scholar
  27. 27.
    Johnstone TB, Agarwal SR, Harvey RD, Ostrom RS (2017) cAMP signaling compartmentation: adenylyl cyclases as anchors of dynamic signaling complexes. Mol Pharmacol 93:270–276.  https://doi.org/10.1124/mol.117.110825 CrossRefPubMedGoogle Scholar
  28. 28.
    Rich TC, Fagan KA, Nakata H, Schaack J, Cooper DM, Karpen JW (2000) Cyclic nucleotide-gated channels colocalize with adenylyl cyclase in regions of restricted cAMP diffusion. J Gen Physiol 116:147–161CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715.  https://doi.org/10.1126/science.1069982 CrossRefPubMedGoogle Scholar
  30. 30.
    Buck J, Sinclair ML, Schapal L, Cann MJ, Levin LR (1999) Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc Natl Acad Sci U S A 96:79–84CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Steegborn C (2014) Structure, mechanism, and regulation of soluble adenylyl cyclases—similarities and differences to transmembrane adenylyl cyclases. Biochim Biophys Acta 1842:2535–2547.  https://doi.org/10.1016/j.bbadis.2014.08.012 CrossRefPubMedGoogle Scholar
  32. 32.
    Chen Y, Cann MJ, Litvin TN, Iourgenko V, Sinclair ML, Levin LR, Buck J (2000) Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Science 289:625–628CrossRefPubMedGoogle Scholar
  33. 33.
    Jaiswal BS, Conti M (2003) Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa. Proc Natl Acad Sci U S A 100:10676–10681.  https://doi.org/10.1073/pnas.1831008100 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Litvin TN, Kamenetsky M, Zarifyan A, Buck J, Levin LR (2003) Kinetic properties of “soluble” adenylyl cyclase. Synergism between calcium and bicarbonate. J Biol Chem 278:15922–15926.  https://doi.org/10.1074/jbc.M212475200 CrossRefPubMedGoogle Scholar
  35. 35.
    Zippin JH, Chen Y, Nahirney P, Kamenetsky M, Wuttke MS, Fischman DA, Levin LR, Buck J (2003) Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains. FASEB J 17:82–84.  https://doi.org/10.1096/fj.02-0598fje CrossRefPubMedGoogle Scholar
  36. 36.
    Zippin JH, Chen Y, Straub SG, Hess KC, Diaz A, Lee D, Tso P, Holz GG, Sharp GW, Levin LR, Buck J (2013) CO2/HCO3(-)- and calcium-regulated soluble adenylyl cyclase as a physiological ATP sensor. J Biol Chem 288:33283–33291.  https://doi.org/10.1074/jbc.M113.510073 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Valsecchi F, Konrad C, Manfredi G (2014) Role of soluble adenylyl cyclase in mitochondria. Biochim Biophys Acta.  https://doi.org/10.1016/j.bbadis.2014.05.035S0925-4439(14)00163-X
  38. 38.
    Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G (2009) Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9:265–276.  https://doi.org/10.1016/j.cmet.2009.01.012 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Acin-Perez R, Russwurm M, Gunnewig K, Gertz M, Zoidl G, Ramos L, Buck J, Levin LR, Rassow J, Manfredi G, Steegborn C (2011) A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. J Biol Chem 286:30423–30432.  https://doi.org/10.1074/jbc.M111.266379 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Modis K, Panopoulos P, Coletta C, Papapetropoulos A, Szabo C (2013) Hydrogen sulfide-mediated stimulation of mitochondrial electron transport involves inhibition of the mitochondrial phosphodiesterase 2A, elevation of cAMP and activation of protein kinase A. Biochem Pharmacol 86:1311–1319.  https://doi.org/10.1016/j.bcp.2013.08.064 CrossRefPubMedGoogle Scholar
  41. 41.
    Di Benedetto G, Scalzotto E, Mongillo M, Pozzan T (2013) Mitochondrial Ca2+ uptake induces cyclic AMP generation in the matrix and modulates organelle ATP levels. Cell Metab 17:965–975.  https://doi.org/10.1016/j.cmet.2013.05.003 CrossRefPubMedGoogle Scholar
  42. 42.
    Helling S, Vogt S, Rhiel A, Ramzan R, Wen L, Marcus K, Kadenbach B (2008) Phosphorylation and kinetics of mammalian cytochrome c oxidase. Mol Cell Proteomics 7:1714–1724.  https://doi.org/10.1074/mcp.M800137-MCP200 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Acin-Perez R, Salazar E, Brosel S, Yang H, Schon EA, Manfredi G (2009) Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects. EMBO Mol Med 1:392–406.  https://doi.org/10.1002/emmm.200900046 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Adam-Vizi V, Starkov AA (2010) Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis 20(Suppl 2):S413–S426.  https://doi.org/10.3233/JAD-2010-100465 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Di Benedetto G, Pendin D, Greotti E, Pizzo P, Pozzan T (2014) Ca2+ and cAMP cross-talk in mitochondria. J Physiol 592:305–312.  https://doi.org/10.1113/jphysiol.2013.259135 CrossRefPubMedGoogle Scholar
  46. 46.
    Steegborn C, Litvin TN, Hess KC, Capper AB, Taussig R, Buck J, Levin LR, Wu H (2005) A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen. J Biol Chem 280:31754–31759.  https://doi.org/10.1074/jbc.M507144200 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lefkimmiatis K, Leronni D, Hofer AM (2013) The inner and outer compartments of mitochondria are sites of distinct cAMP/PKA signaling dynamics. J Cell Biol 202:453–462.  https://doi.org/10.1083/jcb.201303159 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sardanelli AM, Signorile A, Nuzzi R, Rasmo DD, Technikova-Dobrova Z, Drahota Z, Occhiello A, Pica A, Papa S (2006) Occurrence of A-kinase anchor protein and associated cAMP-dependent protein kinase in the inner compartment of mammalian mitochondria. FEBS Lett 580:5690–5696.  https://doi.org/10.1016/j.febslet.2006.09.020 CrossRefPubMedGoogle Scholar
  49. 49.
    Schwoch G, Trinczek B, Bode C (1990) Localization of catalytic and regulatory subunits of cyclic AMP-dependent protein kinases in mitochondria from various rat tissues. Biochem J 270:181–188CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lochner A, Moolman JA (2006) The many faces of H89: a review. Cardiovasc Drug Rev 24:261–274.  https://doi.org/10.1111/j.1527-3466.2006.00261.x CrossRefPubMedGoogle Scholar
  51. 51.
    Fazal L, Laudette M, Paula-Gomes S, Pons S, Conte C, Tortosa F, Sicard P, Sainte-Marie Y, Bisserier M, Lairez O, Lucas A, Roy J, Ghaleh B, Fauconnier J, Mialet-Perez J, Lezoualc’h F (2017) Multifunctional mitochondrial Epac1 controls myocardial cell death. Circ Res 120:645–657.  https://doi.org/10.1161/CIRCRESAHA.116.309859 CrossRefPubMedGoogle Scholar
  52. 52.
    Wang Z, Liu D, Varin A, Nicolas V, Courilleau D, Mateo P, Caubere C, Rouet P, Gomez AM, Vandecasteele G, Fischmeister R, Brenner C (2016) A cardiac mitochondrial cAMP signaling pathway regulates calcium accumulation, permeability transition and cell death. Cell Death Dis 7:e2198.  https://doi.org/10.1038/cddis.2016.106 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535:551–555.  https://doi.org/10.1038/nature18928 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Schmid A, Sutto Z, Nlend MC, Horvath G, Schmid N, Buck J, Levin LR, Conner GE, Fregien N, Salathe M (2007) Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP. J Gen Physiol 130:99–109.  https://doi.org/10.1085/jgp.200709784 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Bird IM, Hanley NA, Word RA, Mathis JM, McCarthy JL, Mason JI, Rainey WE (1993) Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive aldosterone secretion. Endocrinology 133:1555–1561CrossRefPubMedGoogle Scholar
  56. 56.
    Rainey WE, Bird IM, Mason JI (1994) The NCI-H295 cell line: a pluripotent model for human adrenocortical studies. Mol Cell Endocrinol 100:45–50CrossRefPubMedGoogle Scholar
  57. 57.
    Szanda G, Wisniewski E, Rajki A, Spät A (2018) Mitochondrial cAMP exerts positive feedback on mitochondrial Ca(2+) uptake via the recruitment of Epac. J Cell Sci 131:jcs215178.  https://doi.org/10.1242/jcs.215178 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PhysiologySemmelweis University Medical SchoolBudapestHungary
  2. 2.MTA-SE Laboratory of Molecular Physiology, Semmelweis UniversityHungarian Academy of SciencesBudapestHungary

Personalised recommendations