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

Diabetic stress increases the production of reactive oxygen species (ROS), leading to mitochondrial fragmentation and dysfunction. We hypothesized 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 cause mitochondrial 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 pathway may operate in aging-associated illnesses in which excessive mitochondrial fragmentation plays a central role.