Research ArticleCell Biology

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

See allHide authors and affiliations

Sci. Signal.  01 Aug 2017:
Vol. 10, Issue 490, eaal4161
DOI: 10.1126/scisignal.aal4161

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Fragmented by diabetic stress

The high circulating glucose concentrations characteristic of diabetes induce the excessive production of reactive oxygen species (ROS), which triggers mitochondrial fragmentation. The cation channel TRPM2 is activated by ROS, leading Abuarab et al. to investigate the role of this channel in mitochondrial fragmentation in endothelial cells, which become dysfunctional in diabetics. In response to high glucose–induced oxidative stress, Ca2+ influx through TRPM2 channels caused lysosomal permeabilization and redistribution of lysosomal Zn2+ to mitochondria. The increase in mitochondrial Zn2+ led to the recruitment of the fission factor Drp-1, resulting in mitochondrial fragmentation. This pathway may play a role in the pathology of aging-associated diseases that are characterized by increased mitochondrial fragmentation.


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.

View Full Text