High glucose-induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn 2+ -mediated mitochondrial fission

• Published in: Science signaling 2017-08, Vol.10 (490)
• Main Authors: Abuarab, Nada, Munsey, Tim S, Jiang, Lin-Hua, Li, Jing, Sivaprasadarao, Asipu
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Calcium - metabolism; Cell Membrane Permeability - drug effects; Cells, Cultured; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Glucose - metabolism; Humans; Intracellular Membranes - metabolism; Lysosomes - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Dynamics - drug effects; Oxidative Stress; Reactive Oxygen Species - metabolism; Signal Transduction; TRPM Cation Channels - physiology; Zinc - metabolism
• ISSN: 1945-0877; 1937-9145
• DOI: 10.1126/scisignal.aal4161

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 H O induced mitochondrial fission. Ca that entered through TRPM2 induced lysosomal membrane permeabilization, which led to the release of lysosomal Zn and a subsequent increase in mitochondrial Zn Zn 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.