Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease.
Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease.
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DOI：
10.1038/cdd.2011.74
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发表时间：
2011-12
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
PTEN诱导的激酶1（PINK1）突变与帕金森病（PD）相关的家族综合征有关。我们先前报道了内源性PINK1表达减少的稳定的神经母细胞瘤SH-SY5Y细胞系表现出线粒体片段化，增加的线粒体衍生的超氧化物，诱导代偿性巨自噬/线粒体自噬和低水平的持续细胞死亡。在这里，我们研究了蛋白激酶A（PKA）在该模型中提供保护的能力，重点关注其亚细胞靶向。或者：1）用药理学PKA激活剂治疗; 2）瞬时表达一种组成型活性形式的PKA靶向蛋白;或3）瞬时表达野生型AKAP 1，一种将内源性PKA靶向线粒体的支架，逆转了SH-SY5Y细胞中归因于PINK 1丢失的每种表型，并挽救了线粒体呼吸功能障碍的参数。来自PINK1敲除小鼠或经历PINK1 RNAi的原代皮层神经元中的线粒体和溶酶体变化也通过PKA的活化而逆转。PKA使大鼠动力蛋白相关蛋白1亚型1（Drp 1）在丝氨酸656（与人丝氨酸637同源）处磷酸化，抑制其促分裂功能。模拟Drp 1的磷酸化重现了AKAP 1/PKA的许多保护作用。这些数据表明，将内源性PKA重定向到线粒体可以弥补PINK1功能的缺陷，突出了区室化信号网络在线粒体质量控制中的重要性。
Mutations in PTEN-induced kinase 1 (PINK1) are associated with a familial syndrome related to Parkinson’s disease (PD). We previously reported that stable neuroblastoma SH-SY5Y cell lines with reduced expression of endogenous PINK1 exhibit mitochondrial fragmentation, increased mitochondria-derived superoxide, induction of compensatory macroautophagy/mitophagy and a low level of ongoing cell death. Here, we investigated the ability of protein kinase A (PKA) to confer protection in this model, focusing on its subcellular targeting. Either: 1) treatment with pharmacological PKA activators; 2) transient expression of a constitutively active form of mitochondria-targeted PKA; or 3) transient expression of wild-type AKAP1, a scaffold that targets endogenous PKA to mitochondria, reversed each of the phenotypes attributed to loss of PINK1 in SH-SY5Y cells, and rescued parameters of mitochondrial respiratory dysfunction. Mitochondrial and lysosomal changes in primary cortical neurons derived from PINK1 knockout mice or subjected to PINK1 RNAi were also reversed by activation of PKA. PKA phosphorylates the rat dynamin-related protein 1 isoform 1 (Drp1) at serine 656 (homologous to human serine 637), inhibiting its pro-fission function. Mimicking phosphorylation of Drp1 recapitulated many of the protective effects of AKAP1/PKA. These data indicate that redirecting endogenous PKA to mitochondria can compensate for deficiencies in PINK1 function, highlighting the importance of compartmentalized signaling networks in mitochondrial quality control.
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帕金森氏病的线粒体激酶：神经毒素和遗传模型的融合见解。
影响因子：
4.4
作者：
Dagda, Ruben K.;Zhu, Jianhui;Chu, Charleen T.
通讯作者：
Chu, Charleen T.
DOI：
10.1083/jcb.201002108
发表时间：
2010-08-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cherra SJ 3rd;Kulich SM;Uechi G;Balasubramani M;Mountzouris J;Day BW;Chu CT
通讯作者：
Chu CT
DOI：
10.1073/pnas.0705363105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Haque, M. Emdadul;Thomas, Kelly J.;Park, David S.
通讯作者：
Park, David S.
影响因子：
4.8
作者：
Affaitati, A;Cardone, L;Feliciello, A
通讯作者：
Feliciello, A
影响因子：
5.6
作者：
Ginsberg, MD;Feliciello, A;Gottesman, ME
通讯作者：
Gottesman, ME