LRRK2 deficiency induced mitochondrial Ca2+ efflux inhibition can be rescued by Na+/Ca2+/Li+ exchanger upregulation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-04

AUTHORS

Marthe H. R. Ludtmann, Marko Kostic, Amy Horne, Sonia Gandhi, Israel Sekler, Andrey Y. Abramov

ABSTRACT

Variants of leucine-rich repeat kinase 2 (lrrk2) are associated with an increased risk in developing Parkinson's disease (PD). Mitochondrial dysfunction and specifically mitochondrial Ca2+ handling has been linked to the pathogenesis of PD. Here we describe for the second time a mitochondrial Ca2+ efflux deficiency in a model displaying alterations in a PD-associated risk protein. LRRK2 deletion, inhibition and mutations led to an impaired mitochondrial Ca2+ extrusion via Na+/Ca2+/Li+ exchanger (NCLX) which in turn lowered mitochondrial permeability transition pore (PTP) opening threshold and increased cell death. The mitochondrial membrane potential was found not to be the underlying cause for the Ca2+ extrusion deficiency. NCLX activity was rescued by a direct (phosphomimetic NCLX mutant) and indirect (protein kinase A) activation which in turn elevated the PTP opening threshold. Therefore, at least two PD-associated risk protein pathways appear to converge on NCLX controlling mitochondrial Ca2+ extrusion and therefore mitochondrial health. Since mitochondrial Ca2+ overload has been described in many neurological disorders this study warrants further studies into NCLX as a potential therapeutic target. More... »

PAGES

265

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41419-019-1469-5

DOI

http://dx.doi.org/10.1038/s41419-019-1469-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112850092

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30890692


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