10779/crick.11372016.v1
Marthe HR Ludtmann
Marthe HR
Ludtmann
Marko Kostic
Marko
Kostic
Amy Horne
Amy
Horne
Sonia Gandhi
Sonia
Gandhi
Israel Sekler
Israel
Sekler
Andrey Y Abramov
Andrey Y
Abramov
LRRK2 deficiency induced mitochondrial Ca2+ efflux inhibition can be rescued by Na+/Ca2+/Li+ exchanger upregulation
The Francis Crick Institute
2019
Gandhi - sec
1112 Oncology and Carcinogenesis
0601 Biochemistry and Cell Biology
2019-12-16 17:36:07
Journal contribution
https://crick.figshare.com/articles/journal_contribution/LRRK2_deficiency_induced_mitochondrial_Ca2_efflux_inhibition_can_be_rescued_by_Na_Ca2_Li_exchanger_upregulation/11372016
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.