Abstract
Mitochondrial Na+/Ca2+ exchange (NCXmito) is critical for neuronal Ca2+ homeostasis and prevention of cell death from excessive mitochondrial Ca2+ (m[Ca2+]) accumulation. The mitochondrial kinase PINK1 appears to regulate the mCa2+ efflux from dopaminergic (DAergic) neurons, possibly by directly regulating NCXmito. However, the precise molecular identity of NCXmito is unknown and has been the subject of great controversy. Here we propose that the previously characterised plasmalemmal NCX isoforms (NCX2, NCX3) contribute to mitochondrial Na+/Ca2+ exchange in human DAergic neurons and may act downstream of PINK1 in the prevention of neurodegeneration by m[Ca2+] accumulation. Firstly, we definitively show the existence of a mitochondrial pool of endogenous plasmalemmal NCX isoforms in human DAergic neurons and cell lines using immunolocalisation and fluorescence-assisted organelle sorting (FAOS). Secondly, we demonstrate reduced mitochondrial Ca2+ efflux occurs following inhibition of NCX2 or NCX3 (but not NCX1) using siRNA or antibody blocking. This study has potentially revealed a new molecular target in Parkinson’s disease pathology which ultimately may open up new avenues for future therapeutic intervention.
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References
A.Y. Abramov, M. Gegg, A. Grunewald, N.W. Wood, C. Klein, A.H. Schapira, Bioenergetic consequences of PINK1 mutations in Parkinson disease. PLoS One 6, e25622 (2011)
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)
T. Cali, D. Ottolini, M. Brini, Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson’s disease. Biofactors 37, 228–240 (2011)
P. Castaldo, M. Cataldi, S. Magi, V. Lariccia, S. Arcangeli, S. Amoroso, Role of the mitochondrial sodium/calcium exchanger in neuronal physiology and in the pathogenesis of neurological diseases. Prog. Neurobiol. 87, 58–79 (2009)
A. Czyz, L. Kiedrowski, Inhibition of plasmalemmal Na+/Ca2+ exchange by mitochondrial Na+/Ca2+ exchange inhibitor 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3 H)-one (CGP-37157) in cerebellar granule cells. Biochem. Pharmacol. 66, 2409–2411 (2003)
E. Deas, H. Plun-Favreau, S. Gandhi, H. Desmond, S. Kjaer, S.H. Loh, A.E. Renton, R.J. Harvey, A.J. Whitworth, L.M. Martins, A.Y. Abramov, N.W. Wood, PINK1 cleavage at position A103 by the mitochondrial protease PARL. Hum. Mol. Genet. 20, 867–879 (2011)
R. Donato, E.A. Miljan, S.J. Hines, S. Aouabdi, K. Pollock, S. Patel, F.A. Edwards, J.D. Sinden, Differential development of neuronal physiological responsiveness in two human neural stem cell lines. BMC Neurosci. 8, 36 (2007)
I. Drago, P. Pizzo, T. Pozzan, After half a century mitochondrial calcium in- and efflux machineries reveal themselves. EMBO J. 30, 4119–4125 (2011)
S. Gandhi, M.M. Muqit, L. Stanyer, D.G. Healy, P.M. Abou-Sleiman, I. Hargreaves, S. Heales, M. Ganguly, L. Parsons, A.J. Lees, D.S. Latchman, J.L. Holton, N.W. Wood, T. Revesz, PINK1 protein in normal human brain and Parkinson’s disease. Brain 129, 1720–1731 (2006)
S. Gandhi, A. Wood-Kaczmar, Z. Yao, H. Plun-Favreau, E. Deas, K. Klupsch, J. Downward, D.S. Latchman, S.J. Tabrizi, N.W. Wood, M.R. Duchen, A.Y. Abramov, PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol. Cell 33, 627–638 (2009)
P. Gobbi, P. Castaldo, A. Minelli, S. Salucci, S. Magi, E. Corcione, S. Amoroso, Mitochondrial localization of Na+/Ca2+ exchangers NCX1-3 in neurons and astrocytes of adult rat brain in situ. Pharmacol. Res. 56, 556–565 (2007)
W. Li, Z. Shariat-Madar, M. Powers, X. Sun, R.D. Lane, K.D. Garlid, Reconstitution, identification, purification, and immunological characterization of the 110-kDa Na+/Ca2+ antiporter from beef heart mitochondria. J. Biol. Chem. 267, 17983–17989 (1992)
B. Linck, Z. Qiu, Z. He, Q. Tong, D.W. Hilgemann, K.D. Philipson, Functional comparison of the three isoforms of the Na+/Ca2+ exchanger (NCX1, NCX2, NCX3). Am. J. Physiol. 274, C415–C423 (1998)
J. Lytton, Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. Biochem. J. 406, 365–382 (2007)
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)
A. Pilsl, K.F. Winklhofer, Parkin, PINK1 and mitochondrial integrity: emerging concepts of mitochondrial dysfunction in Parkinson’s disease. Acta Neuropathol. 123, 173–188 (2012)
K. Szydlowska, M. Tymianski, Calcium, ischemia and excitotoxicity. Cell Calcium 47, 122–129 (2010)
T. Thurneysen, D.A. Nicoll, K.D. Philipson, H. Porzig, Immunohistochemical detection of the sodium-calcium exchanger in rat hippocampus cultures using subtype-specific antibodies. Ann. N. Y. Acad. Sci. 976, 367–375 (2002)
E.M. Valente, P.M. Abou-Sleiman, V. Caputo, M.M. Muqit, K. Harvey, S. Gispert, Z. Ali, D. Del Turco, A.R. Bentivoglio, D.G. Healy, A. Albanese, R. Nussbaum, R. Gonzalez-Maldonado, T. Deller, S. Salvi, P. Cortelli, W.P. Gilks, D.S. Latchman, R.J. Harvey, B. Dallapiccola, G. Auburger, N.W. Wood, Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304, 1158–1160 (2004)
A. Wood-Kaczmar, S. Gandhi, Z. Yao, A.Y. Abramov, E.A. Miljan, G. Keen, L. Stanyer, I. Hargreaves, K. Klupsch, E. Deas, J. Downward, L. Mansfield, P. Jat, J. Taylor, S. Heales, M.R. Duchen, D. Latchman, S.J. Tabrizi, N.W. Wood, PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS One 3, e2455 (2008)
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Wood-Kaczmar, A., Deas, E., Wood, N.W., Abramov, A.Y. (2013). The Role of the Mitochondrial NCX in the Mechanism of Neurodegeneration in Parkinson’s Disease. 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_20
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