The Role of the Mitochondrial NCX in the Mechanism of Neurodegeneration in Parkinson’s Disease
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.
KeywordsPINK1 Mitochondria NCX Calcium Parkinson’s disease
- 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)PubMedCrossRefGoogle Scholar
- 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)PubMedCrossRefGoogle 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)PubMedCrossRefGoogle Scholar
- 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)PubMedCrossRefGoogle Scholar
- 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)PubMedCrossRefGoogle Scholar