High glucose–induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission

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 in which excessive mitochondrial fragmentation plays a central role.