Institute of Biology and Molecular Genetics (IBGM), Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid and CSIC, Ramón y Cajal, 7, E-47005, Valladolid, Spain.
Institute of Biology and Molecular Genetics (IBGM), Department of Biochemistry and Molecular Biology and Physiology, Faculty of Medicine, University of Valladolid and CSIC, Ramón y Cajal, 7, E-47005, Valladolid, Spain.
Mech Ageing Dev. 2021 Jun;196:111474. doi: 10.1016/j.mad.2021.111474. Epub 2021 Mar 22.
We have reported recently that submaximal inhibition of the Sarco Endoplasmic Reticulum Ca ATPase (SERCA) produces an increase in the lifespan of C. elegans worms. We have explored here the mechanism of this increased survival by studying the effect of SERCA inhibition in several mutants of signaling pathways related to longevity. Our data show that the mechanism of the effect is unrelated with the insulin signaling pathway or the sirtuin activity, because SERCA inhibitors increased lifespan similarly in mutants of these pathways. However, the effect required functional mitochondria and both the AMP kinase and TOR pathways, as the SERCA inhibitors were ineffective in the corresponding mutants. The same effects were obtained after reducing SERCA expression with submaximal RNAi treatment. The SERCA inhibitors did not induce ER-stress at the concentrations used, and their effect was not modified by inactivation of the OP50 bacterial food. Altogether, our data suggest that the effect may be due to a reduced ER-mitochondria Ca transfer acting via AMPK activation and mTOR inhibition to promote survival.
我们最近报道称，肌浆网 Ca2+-ATP 酶（SERCA）的亚最大抑制会导致秀丽隐杆线虫寿命延长。在这里，我们通过研究与长寿相关的信号通路的几种突变体中 SERCA 抑制的作用，探讨了这种存活增加的机制。我们的数据表明，这种作用的机制与胰岛素信号通路或沉默信息调节因子活性无关，因为 SERCA 抑制剂在这些途径的突变体中同样增加了寿命。然而，该作用需要功能线粒体以及 AMP 激酶和 TOR 途径，因为 SERCA 抑制剂在相应的突变体中无效。用亚最大 RNAi 处理降低 SERCA 表达后，也获得了相同的效果。在使用的浓度下，SERCA 抑制剂不会诱导内质网应激，并且其作用不会因 OP50 细菌食物的失活而改变。总的来说，我们的数据表明，这种作用可能是由于 ER-线粒体 Ca2+转移减少所致，通过 AMPK 激活和 mTOR 抑制来促进存活。
