Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.
Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.
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DOI：
10.1371/journal.pgen.1002760
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Haynes CM
中科院分区：
文献类型：
--
作者：
Baker BM;Nargund AM;Sun T;Haynes CM
细胞通过激活恢复内稳态的信号通路来应对线粒体功能的缺陷。线粒体多肽输出因子hIF-1和bZip转录因子ATFS-1是线粒体功能障碍时调节线粒体伴侣基因转录的应激反应途径之一。在这里，我们报告了Gcn-2，一种调节胞浆蛋白合成的eIF2ATFS-2，其功能与HAF-1和α-1的功能互补。在线粒体功能障碍期间，依赖于gcn-2的eif2α的磷酸化是秀丽线虫发育和寿命延长所必需的。依赖GCN-2的eIF2ATFS-1的α磷酸化需要功能障碍的线粒体产生的活性氧物种(ROS)，但不需要。ATFS-1和GCN-2的同时缺失与线粒体应激相关的发育缺陷有关，而缺乏GCN-2的应激动物表现出对ATFS-1的更大依赖和更强的线粒体伴侣基因的诱导。这些发现与UPRmt互补臂中的翻译控制和应激依赖的伴侣诱导是一致的。线粒体功能缺陷与许多与年龄相关的疾病有关，包括癌症和帕金森氏症。线粒体功能依赖于线粒体蛋白质组的维持，线粒体蛋白质组由核和线粒体编码蛋白组成。核编码的多肽在胞浆中被翻译，必须运输到线粒体基质中，在线粒体基质中，驻留的伴侣有助于折叠成其功能构象。为了防止由于错误折叠或未折叠的线粒体蛋白的积累而引起的功能障碍，细胞使用机制来维持折叠环境。其中一个这样的信号通路是由bZip转录因子ATFS-1介导的，它上调线粒体伴侣以适应压倒性的错误折叠蛋白负载。在这里，我们描述了一条互补的途径，将线粒体的功能状态与胞质蛋白质合成的速度结合起来，以保护细胞器在线粒体应激期间免受未折叠蛋白质底物的影响。该途径受胞浆蛋白激酶Gcn-2的调节，它使翻译起始因子2α(eIF2α)亚单位磷酸化，从而减缓一般翻译的速度。GCN-2在线粒体应激过程中对功能障碍的线粒体释放的ROS作出反应，以促进生长和延长寿命。
Cells respond to defects in mitochondrial function by activating signaling pathways that restore homeostasis. The mitochondrial peptide exporter HAF-1 and the bZip transcription factor ATFS-1 represent one stress response pathway that regulates the transcription of mitochondrial chaperone genes during mitochondrial dysfunction. Here, we report that GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1. During mitochondrial dysfunction, GCN-2–dependent eIF2α phosphorylation is required for development as well as the lifespan extension observed in Caenorhabditis elegans. Reactive oxygen species (ROS) generated from dysfunctional mitochondria are required for GCN-2–dependent eIF2α phosphorylation but not ATFS-1 activation. Simultaneous deletion of ATFS-1 and GCN-2 compounds the developmental defects associated with mitochondrial stress, while stressed animals lacking GCN-2 display a greater dependence on ATFS-1 and stronger induction of mitochondrial chaperone genes. These findings are consistent with translational control and stress-dependent chaperone induction acting in complementary arms of the UPRmt. Defects in mitochondrial function are associated with numerous age-related diseases including cancer and Parkinson's. Mitochondrial function relies upon maintenance of the mitochondrial proteome, which is comprised of nuclear and mitochondrial-encoded proteins. Nuclear-encoded polypeptides are translated in the cytosol and must be transported into the mitochondrial matrix, where resident chaperones facilitate folding into their functional conformation. In order to protect against dysfunction arising from an accumulation of misfolded or unfolded mitochondrial proteins, cells employ mechanisms to maintain the folding environment. One such signaling pathway is mediated by the bZip transcription factor ATFS-1, which upregulates mitochondrial chaperones to accommodate an overwhelming misfolded protein load. Here, we describe a complementary pathway that couples the mitochondrial functional status with the rate of cytosolic protein synthesis to protect the organelle from incoming unfolded protein substrates during mitochondrial stress. This pathway is regulated by the cytosolic kinase GCN-2, which phosphorylates the translation initiation factor 2α (eIF2α) subunit to slow general translation. GCN-2 responds to ROS emitted from dysfunctional mitochondria to promote growth and extend lifespan during mitochondrial stress.
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影响因子：
7.8
作者：
Hansen, Malene;Taubert, Stefan;Kenyon, Cynthia
通讯作者：
Kenyon, Cynthia
影响因子：
11.8
作者：
Haynes, Cole M.;Petrova, Kseniya;Ron, David
通讯作者：
Ron, David
DOI：
10.1006/scel.1994.1049
发表时间：
1994-01-01
期刊：
Seminars in Cell Biology
影响因子：
--
作者：
Hinnebusch, Alan G.
通讯作者：
Hinnebusch, Alan G.
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
影响因子：
64.5
作者：
Durieux J;Wolff S;Dillin A
通讯作者：
Dillin A