title: The role of the mitochondrial NCX in the mechanism of neurodegeneration in Parkinson's disease.
abstract: Mitochondrial Na(+)/Ca(2+) exchange (NCXmito) is critical for neuronal Ca(2+) homeostasis and prevention of cell death from excessive mitochondrial Ca(2+) (m[Ca(2+)]) accumulation. The mitochondrial kinase PINK1 appears to regulate the mCa(2+) 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(+)/Ca(2+) exchange in human DAergic neurons and may act downstream of PINK1 in the prevention of neurodegeneration by m[Ca(2+)] 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 Ca(2+) 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.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Wood-Kaczmar
authors.forename: Emma
authors.initials: E
authors.lastname: Deas
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002118:Calcium; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D011494:Protein Kinases; D019831:Sodium-Calcium Exchanger; D000099202:PTEN-Induced Putative Kinase; C101832:SLC38A3 protein, human; C110374:sodium-calcium exchanger 1