Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress
Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress
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DOI：
10.4161/auto.4625
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发表时间：
2007-11-01
期刊：
影响因子：
13.3
通讯作者：
Dagda, Ruben
中科院分区：
文献类型：
--
作者：
Chu, Charleen T.;Zhu, Jianhui;Dagda, Ruben
越来越多的证据支持失调的巨噬（自噬应激）在神经元细胞死亡和神经退行性变中起积极作用。线粒体功能和动力学的改变也与神经退行性疾病密切相关。有趣的是，尽管核心的自噬机制在进化上是保守的，并且在构成性、诱导性或选择性自噬中是共享的，但最近的研究表明，在一般自噬刺激下，调节线粒体自噬（mitophagy）的机制是不同的。关于调节选择性损伤诱导的有丝分裂的途径，我们所知甚少。我们发现帕金森神经毒素MPP+诱导自噬和线粒体降解，这种降解被自噬蛋白Atg5、Atg7和Atg8的siRNA敲除所抑制，但独立于III类（PIK3C3/Vps34）磷酸肌苷激酶（PI3K）复合体的组分Beclin 1发生。相反，MPP+诱导的有丝分裂依赖于MAPK信号。有趣的是，所有抑制自噬的治疗也能保护MPP+诱导的细胞死亡。先前的一项人体组织研究进一步支持ERK/ mapk调节的自噬在帕金森病和路易体疾病中的作用。由于竞争限制Beclin 1的量可能有助于防止有害的自噬过度激活，了解绕过或补充PI3K-Beclin 1活性需求的机制可能导致调节损伤或退化神经元自噬应激的策略。
Growing evidence supports an active role for dysregulated macroautophagy (autophagic stress) in neuronal cell death and neurodegeneration. Alterations in mitochondrial function and dynamics are also strongly implicated in neurodegenerative diseases. Interestingly, whereas the core autophagy machinery is evolutionarily conserved and shared among constitutive and induced or selective autophagy, recent studies implicate distinct mechanisms regulating mitochondrial autophagy (mitophagy) in response to general autophagic stimuli. Little is known about pathways regulating selective, damage-induced mitophagy. We found that the parkinsonian neurotoxin MPP+ induces autophagy and mitochondrial degradation that is inhibited by siRNA knockdown of autophagy proteins Atg5, Atg7 and Atg8, but occurs independently of Beclin 1, a component of the class III (PIK3C3/Vps34) phosphoinositide 3-kinase (PI3K) complex. Instead, MPP+-induced mitophagy is dependent upon MAPK signaling. Interestingly, all treatments that inhibited autophagy also conferred protection from MPP+-induced cell death. A prior human tissue study further supports a role for ERK/MAPK-regulated autophagy in Parkinson's and Lewy body diseases. As competition for limiting amounts of Beclin 1 may serve to prevent harmful overactivation of autophagy, understanding mechanisms that bypass or complement a requirement for PI3K-Beclin 1 activity could lead to strategies to modulate autophagic stress in injured or degenerating neurons.