Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression.
Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression.
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DOI：
10.1016/j.nbd.2013.10.021
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发表时间：
2014-02
影响因子：
6.1
通讯作者：
Schapira AH
中科院分区：
文献类型：
--
作者：
Gómez-Sánchez R;Gegg ME;Bravo-San Pedro JM;Niso-Santano M;Alvarez-Erviti L;Pizarro-Estrella E;Gutiérrez-Martín Y;Alvarez-Barrientos A;Fuentes JM;González-Polo RA;Schapira AH
pten诱导的激酶1 （PINK1）基因突变是常染色体隐性帕金森病（PD）的一个原因。该基因编码线粒体丝氨酸/苏氨酸激酶，部分定位于线粒体，并已被证明在保护神经元细胞免受氧化应激和细胞死亡方面发挥作用，可能与其在线粒体动力学和线粒体自噬中的作用有关。在这项研究中，我们报道了在羰基氰化物间氯酰腙（CCCP）处理后，在人神经母细胞瘤SH-SY5Y细胞中观察到线粒体PINK1水平的增加，这是由于蛋白质的重新合成，而不仅仅是全长PINK1 （FL-PINK1）的稳定性增加。24 h后，细胞的PINK1 mRNA水平显著升高了4倍。尽管线粒体含量降低了29%，但该时间点的FL-PINK1蛋白水平显著高于对照处理或CCCP处理3 h的细胞。我们还表明，CCCP耗散线粒体膜电位（Δψm）并诱导细胞外钙通过L/ n型钙通道进入。钙螯合剂BAPTA-AM破坏cccp诱导的PINK1 mRNA和蛋白表达。此外，CCCP处理以钙依赖的方式激活转录因子c-Fos。这些数据表明，在cccp诱导的有丝分裂中，PINK1的表达以钙依赖的方式显著增加。在Parkin线粒体易位达到峰值后，这种表达的增加仍在继续，这表明PINK1在线粒体底物泛素化下游的线粒体自噬中发挥作用。这种对细胞内钙水平的敏感性支持了PINK1也可能在细胞钙稳态和神经保护中发挥作用的假设。CCCP通过更高的基因表达增加FL-PINK1，即使在有丝分裂诱导后也是如此。PINK1基因表达的增加依赖于钙介导的信号传导。CCCP通过L-和n - vdcs产生细胞外钙。CCCP以钙依赖的方式激活转录因子c-Fos。CCCP通过钙依赖性信号诱导有丝分裂，但不依赖于c- fos。
Mutations of the PTEN-induced kinase 1 (PINK1) gene are a cause of autosomal recessive Parkinson's disease (PD). This gene encodes a mitochondrial serine/threonine kinase, which is partly localized to mitochondria, and has been shown to play a role in protecting neuronal cells from oxidative stress and cell death, perhaps related to its role in mitochondrial dynamics and mitophagy. In this study, we report that increased mitochondrial PINK1 levels observed in human neuroblastoma SH-SY5Y cells after carbonyl cyanide m-chlorophelyhydrazone (CCCP) treatment were due to de novo protein synthesis, and not just increased stabilization of full length PINK1 (FL-PINK1). PINK1 mRNA levels were significantly increased by 4-fold after 24 h. FL-PINK1 protein levels at this time point were significantly higher than vehicle-treated, or cells treated with CCCP for 3 h, despite mitochondrial content being decreased by 29%. We have also shown that CCCP dissipated the mitochondrial membrane potential (Δψm) and induced entry of extracellular calcium through L/N-type calcium channels. The calcium chelating agent BAPTA-AM impaired the CCCP-induced PINK1 mRNA and protein expression. Furthermore, CCCP treatment activated the transcription factor c-Fos in a calcium-dependent manner. These data indicate that PINK1 expression is significantly increased upon CCCP-induced mitophagy in a calcium-dependent manner. This increase in expression continues after peak Parkin mitochondrial translocation, suggesting a role for PINK1 in mitophagy that is downstream of ubiquitination of mitochondrial substrates. This sensitivity to intracellular calcium levels supports the hypothesis that PINK1 may also play a role in cellular calcium homeostasis and neuroprotection. CCCP increases FL-PINK1 by higher gene expression, even after mitophagy induction. The increase in PINK1 gene expression is dependent on calcium-mediated signaling. CCCP produces extracellular calcium entry through L- and N-VDCCs. CCCP activates the transcription factor c-Fos in a calcium-dependent manner. CCCP induces mitophagy by calcium-dependent signaling, but c-Fos-independent.
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影响因子：
5.5
作者：
Buckler, KJ;Vaughan-Jones, RD
通讯作者：
Vaughan-Jones, RD
影响因子：
3.7
作者：
Akundi RS;Huang Z;Eason J;Pandya JD;Zhi L;Cass WA;Sullivan PG;Büeler H
通讯作者：
Büeler H
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
3.7
作者：
Abramov AY;Gegg M;Grunewald A;Wood NW;Klein C;Schapira AH
通讯作者：
Schapira AH
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.