Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner
Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner
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DOI：
10.1016/j.bbamcr.2012.08.007
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发表时间：
2012-12-01
影响因子：
5.1
通讯作者：
Reichert, Andreas S.
中科院分区：
文献类型：
--
作者：
Frank, Magdalena;Duvezin-Caubet, Stephane;Reichert, Andreas S.
线粒体功能障碍与细胞凋亡、衰老、癌症和许多神经退行性疾病和肌肉疾病有关。线粒体自噬和线粒体动力学之间的相互作用与去除功能失调的线粒体有关，以确保线粒体质量控制。一个悬而未决的问题是线粒体分裂在轻度和短暂的氧化应激后线粒体的去除中起着什么作用;据报道，这种情况会导致与体力活动相当的活性氧（ROS）水平中度升高。在这里，我们表明，应用这样的条件导致线粒体片段化和诱导小鼠和人类细胞的线粒体自噬。这些条件仅轻微增加ROS水平，既不引发细胞死亡，也不导致可检测的非选择性自噬诱导。饥饿导致线粒体过度融合，高ROS水平，诱导非选择性自噬和较小程度的线粒体自噬。我们的结论是，中等水平的ROS特异性触发线粒体自噬，但不足以触发非选择性自噬。显性负变异的裂变因子DRP 1的表达阻断了轻度氧化应激以及饥饿诱导的线粒体自噬。两者合计，我们表明，在哺乳动物细胞中，在温和的氧化应激下的DRP 1依赖型的线粒体自噬被触发，而伴随的非选择性自噬诱导没有观察到。我们建议，这些温和的氧化条件下，以及类似的生理情况，因此非常有助于研究的分子途径，管理功能障碍的线粒体的选择性去除。(C)2012 Elsevier B. V.保留所有权利。
Mitochondrial dysfunction is linked to apoptosis, aging, cancer, and a number of neurodegenerative and muscular disorders. The interplay between mitophagy and mitochondrial dynamics has been linked to the removal of dysfunctional mitochondria ensuring mitochondrial quality control. An open question is what role mitochondrial fission plays in the removal of mitochondria after mild and transient oxidative stress; conditions reported to result in moderately elevated reactive oxygen species (ROS) levels comparable to physical activity. Here we show that applying such conditions led to fragmentation of mitochondria and induction of mitophagy in mouse and human cells. These conditions increased ROS levels only slightly and neither triggered cell death nor led to a detectable induction of non-selective autophagy. Starvation led to hyperfusion of mitochondria, to high ROS levels, and to the induction of both non-selective autophagy and to a lesser extent to mitophagy. We conclude that moderate levels of ROS specifically trigger mitophagy but are insufficient to trigger non-selective autophagy. Expression of a dominant-negative variant of the fission factor DRP1 blocked mitophagy induction by mild oxidative stress as well as by starvation. Taken together, we demonstrate that in mammalian cells under mild oxidative stress a DRP1-dependent type of mitophagy is triggered while a concomitant induction of non-selective autophagy was not observed. We propose that these mild oxidative conditions resembling well physiological situations are thus very helpful for studying the molecular pathways governing the selective removal of dysfunctional mitochondria. (C) 2012 Elsevier B.V. All rights reserved.