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.