Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis.
Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis.
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DOI：
10.1016/j.celrep.2020.108125
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发表时间：
2020-09-08
期刊：
影响因子：
8.8
通讯作者：
Mair WB
中科院分区：
文献类型：
--
作者：
Burkewitz K;Feng G;Dutta S;Kelley CA;Steinbaugh M;Cram EJ;Mair WB
单独来看，内质网（ER）和线粒体的功能障碍都与衰老有关，但这些细胞器之间的交流如何以促进长寿为目标尚不清楚。在这里，我们提供的证据表明，在秀丽隐杆线虫中，抑制保守的未折叠蛋白反应（UPRER）介质，激活转录因子(atf)-6，通过调节钙稳态和向线粒体发出信号来延长寿命。Atf-6的损失通过下调内质网钙缓冲物钙网蛋白而延长寿命。内质网钙通过肌醇三磷酸受体（IP3R/itr-1）释放是长寿所必需的，而IP3R/itr-1功能的增加足以延长寿命。强调细胞器之间的协调，线粒体钙输入通道mcu-1也是atf-6长寿所必需的。IP3R抑制导致线粒体生物能量和低灌注受损，这足以抑制atf-6突变体的长寿。本研究揭示了细胞器钙处理作为UPRER在确定老化质量中的关键输出的重要性。Burkewitz等人表明，调节亚细胞钙区隔化和信号传导是衰老和长寿的一种机制。未折叠蛋白反应的保守介质ATF-6的缺失会破坏内质网中的钙潴留；随后，内质网钙释放通过刺激线粒体动力学和功能来延长寿命。
Individually, dysfunction of both the endoplasmic reticulum (ER) and mitochondria has been linked to aging, but how communication between these organelles might be targeted to promote longevity is unclear. Here, we provide evidence that, in Caenorhabditis elegans, inhibition of the conserved unfolded protein response (UPRER) mediator, activating transcription factor (atf)-6, increases lifespan by modulating calcium homeostasis and signaling to mitochondria. Atf-6 loss confers longevity via downregulation of the ER calcium buffer, calreticulin. ER calcium release via the inositol triphosphate receptor (IP3R/itr-1) is required for longevity, while IP3R/itr-1 gain of function is sufficient to extend lifespan. Highlighting coordination between organelles, the mitochondrial calcium import channel mcu-1 is also required for atf-6 longevity. IP3R inhibition leads to impaired mitochondrial bioenergetics and hyperfusion, which is sufficient to suppress long life in atf-6 mutants. This study reveals the importance of organellar calcium handling as a critical output for the UPRER in determining the quality of aging. Burkewitz et al. show that modulating subcellular calcium compartmentalization and signaling is a mechanism of both aging and longevity. The loss of ATF-6, a conserved mediator of the unfolded protein response, disrupts calcium retention in the ER; subsequently, ER calcium release triggers lifespan extension by stimulating mitochondrial dynamics and function.
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