21 May 2020
An old puzzle in diabetes solved
Published online 27 August 2017
Scientists connect the dots on a new signaling cascade in diabetes.
A new study has revealed an unexpected role for the TRPM2 ion channel in relation to diabetes-associated complications.
Ion channels are proteins or protein complexes that gate the flow of ions across cell membranes. They’re present within the membranes of most cells.
Long-term complications of diabetes result from many factors, including increased blood glucose, which in turn can trigger a rise in reactive oxygen species (ROS), a product of oxygen metabolism. High levels of ROS can eventually lead to dysfunctions in the mitochondria, which is the powerhouse of the cell.
The underlying molecular mechanism for this has so far been mysterious until this new study1.
Scientists from the UK and Saudi Arabia show that, in response to increased ROS levels, TRPM2 mediates a rearrangement in the ions' localization within the cell. Particularly, TRPM2 facilitates the flow of zinc ions towards the mitochondria, where those ions stimulate the recruitment of another protein, called Drp-1, to induce the mitochondrial breakdown.
Interestingly, the team also show that when depleting TRPM2 in mice or in cultured cells, these sequential events are not triggered and the mitochondria remains intact even in the presence of high glucose or ROS levels.
"ROS-induced breakdown of the mitochondrial network is not limited to diabetes, but occurs in a wide range of other debilitating diseases that we develop as we age," says principal investigator, Asipu Sivaprasadarao, from the University of Leeds. It’s why this discovery opens up possibilities for developing new therapeutics across a range of diseases.
- Abuarab N. et al. High glucose–induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission. Sci. Signal. http://dx.doi.org/10.1126/scisignal.aal4161 (2017).