Royal Veterinary College, 4 Royal College St, Kings Cross, London, NW1 0TU, UK.
Department of Clinical and Movement Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UK.
Cell Death Dis. 2019 Mar 19;10(4):265. doi: 10.1038/s41419-019-1469-5.
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 handling has been linked to the pathogenesis of PD. Here we describe for the second time a mitochondrial Ca efflux deficiency in a model displaying alterations in a PD-associated risk protein. LRRK2 deletion, inhibition and mutations led to an impaired mitochondrial Ca extrusion via Na/Ca/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 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 extrusion and therefore mitochondrial health. Since mitochondrial Ca overload has been described in many neurological disorders this study warrants further studies into NCLX as a potential therapeutic target.
富含亮氨酸重复激酶 2（LRRK2）的变异与帕金森病（PD）发病风险增加有关。线粒体功能障碍，特别是线粒体 Ca 处理与 PD 的发病机制有关。在这里，我们在第二个模型中描述了与 PD 相关风险蛋白改变相关的线粒体 Ca 外排缺陷。LRRK2 缺失、抑制和突变导致通过 Na/Ca/Li 交换器（NCLX）的线粒体 Ca 外排受损，这反过来又降低了线粒体通透性转换孔（PTP）开放阈值并增加了细胞死亡。发现线粒体膜电位不是 Ca 外排缺陷的根本原因。通过直接（磷酸模拟 NCLX 突变体）和间接（蛋白激酶 A）激活来挽救 NCLX 活性，这反过来又提高了 PTP 开放阈值。因此，至少有两种与 PD 相关的风险蛋白途径似乎都集中在控制线粒体 Ca 外排的 NCLX 上，从而影响线粒体健康。由于许多神经退行性疾病中都描述了线粒体 Ca 过载，因此这项研究证明了 NCLX 作为潜在治疗靶点的进一步研究是合理的。
