Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death
Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death
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DOI：
10.1073/pnas.1114985109
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发表时间：
2012-02-14
影响因子：
11.1
通讯作者：
Yanagi, Shigeru
中科院分区：
文献类型：
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作者：
Yonashiro, Ryo;Kimijima, Yuya;Yanagi, Shigeru
一氧化氮(NO)与神经细胞存活有关。然而，过量的NO产生介导了神经细胞的死亡，部分是通过线粒体功能障碍。在这里，我们报道了线粒体泛素连接酶，丝裂素，保护神经细胞免受S亚硝化微管相关蛋白1B轻链1(Lc1)积聚引起的线粒体损伤。Lc1的S亚硝化引起构象变化，激活Lc1并促进其泛化，表明Lc1通过与Mitol的相互作用来调节微管的稳定。过量的NO产生对丝裂素有抑制作用，在钙霉素和N-甲基-D-天冬氨酸刺激NO产生后，抑制丝裂素可导致S亚硝酸化的Lc1积聚。在此条件下，Lc1积聚导致线粒体功能障碍和神经细胞死亡。因此，S亚硝化激活Lc1和米托尔下调之间的平衡对神经细胞的存活至关重要。我们的发现可能有助于理解由亚硝化应激介导的线粒体功能障碍引起的神经系统疾病的机制。
Nitric oxide (NO) is implicated in neuronal cell survival. However, excessive NO production mediates neuronal cell death, in part via mitochondrial dysfunction. Here, we report that the mitochondrial ubiquitin ligase, MITOL, protects neuronal cells from mitochondrial damage caused by accumulation of S-nitrosylated microtubule-associated protein 1B-light chain 1 (LC1). S-nitrosylation of LC1 induces a conformational change that serves both to activate LC1 and to promote its ubiquination by MITOL, indicating that microtubule stabilization by LC1 is regulated through its interaction with MITOL. Excessive NO production can inhibit MITOL, and MITOL inhibition resulted in accumulation of S-nitrosylated LC1 following stimulation of NO production by calcimycin and N-methyl-D-aspartate. LC1 accumulation under these conditions resulted in mitochondrial dysfunction and neuronal cell death. Thus, the balance between LC1 activation by S-nitrosylation and down-regulation by MITOL is critical for neuronal cell survival. Our findings may contribute significantly to an understanding of the mechanisms of neurological diseases caused by nitrosative stress-mediated mitochondrial dysfunction.