High glucose-induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission
High glucose-induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission
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DOI：
10.1126/scisignal.aal4161
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发表时间：
2017-08-01
影响因子：
7.3
通讯作者：
Sivaprasadarao, Asipu
中科院分区：
文献类型：
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作者：
Abuarab, Nada;Munsey, Tim S.;Sivaprasadarao, Asipu
糖尿病应激增加活性氧（ROS）的产生，导致线粒体断裂和功能障碍。我们推测ROS敏感的TRPM 2通道介导了糖尿病应激诱导的线粒体断裂。我们发现，化学抑制剂、RNAi沉默和TRPM 2通道的基因敲除消除了高糖导致内皮细胞线粒体分裂的能力，内皮细胞是一种特别容易受到糖尿病应激的细胞类型。与高糖相似，通过施加H2 O2增加内皮细胞中的ROS诱导线粒体分裂。通过TRPM 2进入的Ca 2+诱导溶酶体膜透化，这导致溶酶体Zn 2+的释放和随后的线粒体Zn 2+的增加。Zn 2+促进了分裂因子Drp-1向线粒体的募集，从而引发线粒体的分裂。这种信号通路可能在与衰老相关的疾病中起作用，其中过度的线粒体碎片化起着核心作用。
Diabetic stress increases the production of reactive oxygen species (ROS), leading to mitochondrial fragmentation and dysfunction. Wehypothesized that ROS-sensitive TRPM2 channels mediated diabetic stress-induced mitochondrial fragmentation. We found that chemical inhibitors, RNAi silencing, and genetic knockout of TRPM2 channels abolished the ability of high glucose to causemitochondrial fission in endothelial cells, a cell type that is particularly vulnerable to diabetic stress. Similar to high glucose, increasing ROS in endothelial cells by applying H2O2 induced mitochondrial fission. Ca2+ that entered through TRPM2 induced lysosomal membrane permeabilization, which led to the release of lysosomal Zn2+ and a subsequent increase in mitochondrial Zn2+. Zn2+ promoted the recruitment of the fission factor Drp-1 to mitochondria to trigger their fission. This signaling pathwaymay operate in aging-associated illnesses inwhich excessive mitochondrial fragmentation plays a central role.