PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons.
PKA Phosphorylation of NCLX Reverses Mitochondrial Calcium Overload and Depolarization, Promoting Survival of PINK1-Deficient Dopaminergic Neurons.
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DOI：
10.1016/j.celrep.2015.08.079
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发表时间：
2015-10-13
期刊：
影响因子：
8.8
通讯作者：
Sekler I
中科院分区：
文献类型：
--
作者：
Kostic M;Ludtmann MH;Bading H;Hershfinkel M;Steer E;Chu CT;Abramov AY;Sekler I
线粒体Ca2+超载是神经退行性和缺血性损伤期间遇到的神经元损伤的关键，之前的事件。我们发现pten诱导的推定激酶1 （PINK1）功能的丧失与帕金森病有关，抑制线粒体Na+/Ca2+交换器（NCLX），导致线粒体Ca2+挤压受损。然而，NCLX活性通过蛋白激酶A （PKA）途径的激活完全恢复。我们进一步表明，PKA通过磷酸化丝氨酸258（一个假定的NCLX调控位点）来挽救NCLX的活性。值得注意的是，NCLX的组成活性拟磷突变体（NCLXS258D）可防止PINK1敲除神经元中的线粒体Ca2+过载和线粒体去极化，从而提高神经元的存活率。我们的研究结果确定了线粒体Ca2+运输调节途径，防止线粒体Ca2+超载。由于线粒体Ca2+平衡失调是多种疾病的一个突出特征，NCLX和PKA之间的联系可能提供一个治疗靶点。
Mitochondrial Ca2+ overload is a critical, preceding event in neuronal damage encountered during neurodegenerative and ischemic insults. We found that loss of PTEN-induced putative kinase 1 (PINK1) function, implicated in Parkinson disease, inhibits the mitochondrial Na+/Ca2+ exchanger (NCLX), leading to impaired mitochondrial Ca2+ extrusion. NCLX activity was, however, fully rescued by activation of the protein kinase A (PKA) pathway. We further show that PKA rescues NCLX activity by phosphorylating serine 258, a putative regulatory NCLX site. Remarkably, a constitutively active phosphomimetic mutant of NCLX (NCLXS258D) prevents mitochondrial Ca2+ overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca2+ transport regulatory pathway that protects against mitochondrial Ca2+ overload. Because mitochondrial Ca2+ dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target.