Autophagy compensates for defects in mitochondrial dynamics
Autophagy compensates for defects in mitochondrial dynamics
复制标题
DOI：
10.1371/journal.pgen.1008638
复制
发表时间：
2020-03-01
期刊：
影响因子：
4.5
通讯作者：
Conradt, Barbara
中科院分区：
文献类型：
--
作者：
Haeussler, Simon;Koehler, Fabian;Conradt, Barbara
损害线粒体融合或裂变破坏细胞内稳态；然而，其潜在的机制尚不完全清楚。秀丽隐杆线虫fzo-1（MFN）缺失导致线粒体断裂、线粒体膜电位降低和线粒体未折叠蛋白反应（UPRmt）的诱导。我们进行了全基因组RNAi筛选，以寻找敲除fzo-1(MFN)（lf）诱导的UPRmt的基因。在鉴定的299个基因中，143个编码自噬的负调节因子，其中许多先前未涉及这种细胞质量控制机制。我们提供的证据表明，增加的自噬通量通过增加线粒体膜电位而不是恢复线粒体形态来抑制fzo-1(MFN)（lf）诱导的UPRmt。此外，我们还证明，增加的自噬通量也会抑制upmt诱导，以响应线粒体裂变的阻断，但不会响应编码线粒体金属蛋白酶的spg-7（AFG3L2）的丢失。最后，我们发现，阻断线粒体融合或裂变会导致某些类型的甘油三酯水平增加，而这至少部分是通过诱导自噬来恢复的。我们认为这些三酰基甘油通过自噬分解导致代谢活性升高，从而增加线粒体膜电位，恢复线粒体和细胞稳态。细胞内各种质量控制机制确保线粒体稳态。具体来说，线粒体分裂和融合、线粒体未折叠蛋白反应（UPRmt）和/或线粒体自噬是在线粒体应激诱导下维持或恢复线粒体稳态的。这些不同的质量控制机制如何协调，以及它们如何相互影响，目前还不是很清楚。有趣的是，线粒体动力学的破坏最近被证明可以诱导UPRmt。我们对线粒体融合阻滞诱导的UPRmt抑制基因进行了全基因组RNAi筛选，发现大约一半的候选基因被鉴定为负调节自噬，自噬是一种在应激条件下调节细胞代谢的中心质量控制机制。此外，我们发现自噬的诱导也抑制了线粒体分裂阻滞诱导的UPRmt。此外，我们证明线粒体动力学缺陷导致脂质代谢的变化，这可以通过诱导自噬部分恢复。综上所述，我们的研究结果表明，在线粒体动力学缺陷的动物中，UPRmt与自噬之间存在迄今未知的功能联系。
Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1(MFN) results in mitochondrial fragmentation, decreased mitochondrial membrane potential and the induction of the mitochondrial unfolded protein response (UPRmt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1(MFN)(lf)-induced UPRmt. Of the 299 genes identified, 143 encode negative regulators of autophagy, many of which have previously not been implicated in this cellular quality control mechanism. We present evidence that increased autophagic flux suppresses fzo-1(MFN)(lf)-induced UPRmt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPRmt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7(AFG3L2), which encodes a mitochondrial metalloprotease. Finally, we found that blocking mitochondrial fusion or fission leads to increased levels of certain types of triacylglycerols and that this is at least partially reverted by the induction of autophagy. We propose that the breakdown of these triacylglycerols through autophagy leads to elevated metabolic activity, thereby increasing mitochondrial membrane potential and restoring mitochondrial and cellular homeostasis.Author summaryVarious quality control mechanisms within the cell ensure mitochondrial homeostasis. Specifically, mitochondrial fission and fusion, the mitochondrial unfolded protein response (UPRmt) and/or mitophagy are induced upon mitochondrial stress to maintain or restore mitochondrial homeostasis. How these different quality control mechanisms are coordinated and how they influence each other is currently not well understood. Interestingly, the disruption of mitochondrial dynamics has recently been shown to induce UPRmt. We performed a genome-wide RNAi screen for suppressors of UPRmt induced by a block in mitochondrial fusion and found approximately half of the candidate genes identified to negatively regulate autophagy, a central quality control mechanism that adjusts cellular metabolism under conditions of stress. Furthermore, we found that induction of autophagy also suppresses UPRmt induced by a block in mitochondrial fission. In addition, we demonstrate that defects in mitochondrial dynamics lead to changes in lipid metabolism, which can partially be reverted by the induction of autophagy. Taken together, our results suggest a so far unknown functional connection between UPRmt and autophagy in animals with defects in mitochondrial dynamics.