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 Ca(2+) handling has been linked to the pathogenesis of PD. Here we describe for the second time a mitochondrial Ca(2+) efflux deficiency in a model displaying alterations in a PD-associated risk protein. LRRK2 deletion, inhibition and mutations led to an impaired mitochondrial Ca(2+) extrusion via Na(+)/Ca(2+)/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 Ca(2+) 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 Ca(2+) extrusion and therefore mitochondrial health. Since mitochondrial Ca(2+) overload has been described in many neurological disorders this study warrants further studies into NCLX as a potential therapeutic target.