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New Insights in Mitochondrial Calcium Handling by Sodium/Calcium Exchanger

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Sodium Calcium Exchange: A Growing Spectrum of Pathophysiological Implications

Abstract

Mitochondria are now recognized as one of the main intracellular calcium-storing organelles which play a key role in the intracellular calcium signalling. Indeed, besides performing oxidative phosphorylation, mitochondria are able to sense and shape calcium (Ca2+) transients, thus controlling cytosolic Ca2+ signals and Ca2+-dependent protein activity. It has been well established for many years that mitochondria have a huge capacity to accumulate calcium. While the physiological significance of this pathway was hotly debated until relatively recently, it is now clear that the ability of mitochondria in calcium handling is a ubiquitous phenomenon described in every cell system in which the issue has been addressed.

In this chapter, we will review the molecular mechanisms involved in the regulation of mitochondrial calcium cycling in physiological conditions with particular regard to the role played by the mitochondrial Na+/Ca2+ exchanger.

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-4614-4756-6_38

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-1-4614-4756-6_38

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References

  • L. Annunziato, G. Pignataro, G.F. Di Renzo, Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol. Rev. 56, 633–654 (2004)

    Article  PubMed  CAS  Google Scholar 

  • A. Atlante, A. Bobba, P. Calissano, S. Passarella, E. Marra, The apoptosis/necrosis transition in cerebellar granule cells depends on the mutual relationship of the antioxidant and the proteolytic systems which regulate ROS production and cytochrome c release en route to death. J. Neurochem. 84, 960–971 (2003)

    Article  PubMed  CAS  Google Scholar 

  • D.F. Babcock, J. Herrington, P.C. Goodwin, Y.B. Park, B. Hille, Mitochondrial participation in the intracellular Ca2+ network. J. Cell Biol. 136, 833–844 (1997)

    Article  PubMed  CAS  Google Scholar 

  • J.M. Baughman, F. Perocchi, H.S. Girgis, M. Plovanich, C.A. Belcher-Timme, Y. Sancak, X.R. Bao, L. Strittmatter, O. Goldberger, R.L. Bogorad, V. Koteliansky, V.K. Mootha, Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011)

    Article  PubMed  CAS  Google Scholar 

  • P. Bernardi, Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127–1155 (1999)

    Article  PubMed  CAS  Google Scholar 

  • C.H. Berthold, C. Fabricius, M. Rydmark, B. Andersen, Axoplasmic organelles at nodes of Ranvier. I. Occurrence and distribution in large myelinated spinal root axons of the adult cat. J. Neurocytol. 22, 925–940 (1993)

    Article  PubMed  CAS  Google Scholar 

  • E.A. Bristow, P.G. Griffiths, R.M. Andrews, M.A. Johnson, D.M. Turnbull, The distribution of mitochondrial activity in relation to optic nerve structure. Arch. Ophthalmol. 120, 791–796 (2002)

    Article  PubMed  Google Scholar 

  • L. Buntinas, K.K. Gunter, G.C. Sparagna, T.E. Gunter, The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria. Biochim. Biophys. Acta 1504, 248–261 (2001)

    Article  PubMed  CAS  Google Scholar 

  • E. Carafoli, Historical review: mitochondria and calcium: ups and downs of an unusual relationship. Trends Biochem. Sci. 28, 175–181 (2003)

    Article  PubMed  CAS  Google Scholar 

  • E. Carafoli, R. Tiozzo, G. Lugli, F. Crovetti, C. Kratzing, The release of calcium from heart mitochondria by sodium. J. Mol. Cell. Cardiol. 6, 361–371 (1974)

    Article  PubMed  CAS  Google Scholar 

  • M. Chiesi, R. Schwaller, K. Eichenberger, Structural dependency of the inhibitory action of benzodiazepines and related compounds on the mitochondrial Na+-Ca2+ exchanger. Biochem. Pharmacol. 22, 4399–4403 (1988)

    Article  Google Scholar 

  • M. Crompton, E. Barksby, N. Johnson, M. Capano, Mitochondrial intermembrane junctional complexes and their involvement in cell death. Biochimie 84, 143–152 (2002)

    Article  PubMed  CAS  Google Scholar 

  • D.A. Cox, L. Conforti, N. Sperelakis, M.A. Matlib. Selectivity of inhibition of Na(+)-Ca2+ exchange of heart mitochondria by benzothiazepine CGP-37157. J. Cardiovasc. Pharmacol. 21, 595–599 (1993)

    Article  PubMed  CAS  Google Scholar 

  • D. De Stefani, A. Raffaello, E. Teardo, I. Szabo, R. Rizzuto, A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011)

    Article  PubMed  Google Scholar 

  • C. Du, M. Fang, Y. Li, L. Li, X. Wang, Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000)

    Article  PubMed  CAS  Google Scholar 

  • L.L. Dugan, D.W. Choi, Excitotoxicity, free radicals, and cell membrane changes. Ann. Neurol. 35, S17–S21 (1994)

    Article  PubMed  CAS  Google Scholar 

  • M. Erecinska, I.A. Silver, Ions and energy in mammalian brain. Prog. Neurobiol. 43, 37–71 (1994)

    Article  PubMed  CAS  Google Scholar 

  • E.J. Harris, Modulation of Ca2+ efflux from heart mitochondria. Biochem. J. 178, 673–680 (1979)

    PubMed  CAS  Google Scholar 

  • L.S. Jouaville, F. Ichas, E.L. Holmuhamedov, P. Camacho, J.D. Lechleiter, Synchronization of calcium waves by mitochondrial substrates in Xenopus laevis oocytes. Nature 377, 438–441 (1995)

    Article  PubMed  CAS  Google Scholar 

  • G.H. Kageyama, M.T. Wong-Riley, Histochemical localization of cytochrome oxidase in the hippocampus: correlation with specific neuronal types and afferent pathways. Neuroscience 7, 2337–2361 (1982)

    Article  PubMed  CAS  Google Scholar 

  • A.L. Lehninger, A. Vercesi, E.A. Bababunmi, Regulation of Ca2+ release from mitochondria by the oxidation-reduction state of pyridine nucleotides. Proc. Natl. Acad. Sci. U. S. A. 75, 1690–1694 (1978)

    Article  PubMed  CAS  Google Scholar 

  • P. Li, D. Nijhawan, I. Budihardjo, S.M. Srinivasula, M. Ahmad, E.S. Alnemri, X. Wang, Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997)

    Article  PubMed  CAS  Google Scholar 

  • A. Livigni, A. Scorziello, S.Agnese, A. Adornetto, A. Carlucci, C. Garbi, I. Castaldo, L. Annunziato, E.V. Avvedimento, A. Feliciello, Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Mol. Biol. Cell 17, 263–271 (2006)

    Article  PubMed  CAS  Google Scholar 

  • C. Murgia, P. Giorgi, P. Pinton, R. Rizzuto, Controlling metabolism and cell death: at the heart of mitochondrial calcium signaling. J. Mol. Cell. Cardiol. 46, 781–788 (2009)

    Article  PubMed  CAS  Google Scholar 

  • D.G. Nicholls, The regulation of extramitochondrial free calcium ion concentration by rat liver mitochondria. Biochem. J. 176, 463–474 (1978)

    PubMed  CAS  Google Scholar 

  • D.G. Nicholls, Mitochondrial membrane potential and aging. Aging Cell 3, 35–40 (2004)

    Article  PubMed  CAS  Google Scholar 

  • D.G. Nicholls, M. Crompton, Mitochondrial calcium transport. FEBS Lett. 111, 261–268 (1980)

    Article  PubMed  CAS  Google Scholar 

  • S.M. Nicolau, Mitochondrial Na+/Ca2+-exchanger blocker CGP37157 protects against chromaffin cell death elicited by veratridine. J. Pharmacol. Exp. Ther. 330(3), 844–854 (2009)

    Article  PubMed  CAS  Google Scholar 

  • R. Palty, W.F. Silverman, M. Hershfinkel, T. Caporale, S.L. Sensi, J. Parnis, C. Nolte, D. Fishman, V. Shoshan-Barmatz, S. Herrmann, D. Khananshvili, I. Sekler, NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl. Acad. Sci. U. S. A. 107, 436–441 (2010)

    Article  PubMed  CAS  Google Scholar 

  • G. Petrosillo, F.M. Ruggiero, M. Pistolese, G. Paradies, Ca2+-induced reactive oxygen species production promotes cytochrome c release from rat liver mitochondria via mitochondrial permeability transition (MPT)-dependent and MPT-independent mechanisms: role of cardiolipin. J. Biol. Chem. 279, 53103–53108 (2004)

    Article  PubMed  CAS  Google Scholar 

  • C. Ramachandran, F.L. Bygrave, Calcium ion cycling in rat liver mitochondria. Biochem. J. 174, 613–620 (1978)

    PubMed  CAS  Google Scholar 

  • R. Rizzuto, P. Bernardi, T. Pozzan, Mitochondria as all-round players of the calcium game. J. Physiol. 1, 37–47 (2000)

    Article  Google Scholar 

  • K.C. Rowland, N.K. Irby, G.A. Spirou, Specialized synapse-associated structures within the calyx of Held. J. Neurosci. 20, 9135–9144 (2000)

    PubMed  CAS  Google Scholar 

  • N.E. Saris, E. Carafoli, A historical review of cellular calcium handling, with emphasis on mitochondria. Biochemistry (Mosc.) 70, 187–194 (2005)

    Article  CAS  Google Scholar 

  • A. Scorziello, M. Santillo, A. Adornetto, C. Dell’Aversano, R. Sirabella, S. Damiano, L.M. Canzoniero, G.F. Renzo, L. Annunziato, NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via Ras/ERK1/2 pathway. J. Neurochem. 103, 1472–80 (2007)

    Article  CAS  Google Scholar 

  • G.C. Sparagna, K.K. Gunter, S.S. Sheu, T.E. Gunter, Mitochondrial calcium uptake from physiological-type pulses of calcium. A description of the rapid uptake mode. J. Biol. Chem. 270, 27510–27515 (1995)

    Article  PubMed  CAS  Google Scholar 

  • S.A. Susin, H.K. Lorenzo, N. Zamzami, I. Marzo, B.E. Snow, G.M. Brothers, J. Mangion, E. Jacotot, P. Costantini, M. Loeffler, N. Larochette, D.R. Goodlett, R. Aebersold, D.P. Siderovski, J.M. Penninger, G. Kroemer, Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999)

    Article  PubMed  CAS  Google Scholar 

  • G. Szabadkai, M.R. Duchen, Mitochondria: the hub of cellular Ca2+ signaling. Physiology (Bethesda) 23, 84–94 (2008)

    Article  CAS  Google Scholar 

  • A.M. Verhagen, P.G. Ekert, M. Pakusch, J. Silke, L.M. Connolly, G.E. Reid, R.L. Moritz, R.J. Simpson, D.L. Vaux, Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53 (2000)

    Article  PubMed  CAS  Google Scholar 

  • J.L. Werth, S.A. Thayer, Mitochondria buffer physiological calcium loads in cultured rat dorsal root ganglion neurons. J. Neurosci. 14, 348–356 (1994)

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by COFIN2008; Ricerca-Sanitaria RF-FSL352059 Ricerca finalizzata 2006; Ricerca-Oncologica 2006; Progetto-Strategico 2007; Progetto Ordinario 2007; Ricerca finalizzata 2009; Ricerca-Sanitaria progetto Ordinario by Ministero della Salute 2008 all to LA

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Correspondence to Lucio Annunziato M.D. .

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Scorziello, A. et al. (2013). New Insights in Mitochondrial Calcium Handling by Sodium/Calcium Exchanger. In: Annunziato, L. (eds) Sodium Calcium Exchange: A Growing Spectrum of Pathophysiological Implications. Advances in Experimental Medicine and Biology, vol 961. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4756-6_17

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