Dr. Simmen Discovers A Mechanism of Rare Epileptic Syndrome Depends on Aberrant Cell Stress Control
3 November 2025
As any cell biologist knowns, the Endoplasmic Reticulum (ER) is the machinery for protein folding. When times are good, the ER works without a hitch. But when physiologic or pathologic stresses occur, the gears in the machine may end up having to go into overdrive as the need for more proteins and more protein folding becomes greater than the capacity to do so. Mixups occur leading to unfolded and misfolded proteins. As those build up, the ER becomes stressed as it simply cannot continue to perform as expected. Without alleviation of that stress, the cell is doomed and will eventually undergo apoptosis.
No one wants that.
Thankfully, there is an effective stress reliever in the cell that involves another critical organelle - the mitochondrion. They can connect physically - known as ER-Mitochondria Contact Sites (ERMCS) - and create tiny communication hubs essential for decreasing that stress by providing more mitochondrial energy. Of course, while we know of these sites and the effect they have on the cell, the how behind this process hasn't been fully understood. Now Dr Thomas Simmen has provided an inside look at how ERMCS regulate stress relief and what happens when that stress relief is overactive in a rare brain development disease.
Dr. Simmen has identified the protein thioredoxin-related transmembrane protein 2 (TMX2) as a critical player in this cellular stress management system. TMX2 interacts directly with the mitochondrial tethering protein, TOM70. Normally, they work together to maintain space between the two organelles to control mitochondrial energy output. This prevents an influx of calcium from the stressed ER into the mitochondrion that can lead to a vicious cycle of more stress. TMX2 also helps to prevent a rather unwelcome reaction between TOM70 and one of the molecules associated with ER stress, hydrogen peroxide. The peroxide can change the structure of TOM70 through a process called sulfenylation leading to a shortening of the gap between the organelles and that unfortunate influx of calcium. As a consequence, mitochondria can produce abnormally high energy levels.
While this mechanism is an important discovery, the impact of this knowledge is much greater. There is already a known disease associated with TMX2 failure - it's Neurodevelopmental Disorder with Microcephaly, Cortical Malformations, and Spasticity (NEDMCMS). It's known as a developmental epileptic encephalopathy and is associated with seizures and microcephaly. Using fibroblasts from patients, Dr. Simmen reveals that the same effects seen in the lab also appear to be occurring in these patients - their cells had smaller gaps between the ER and the mitochondria, resulting in overactive mitochondria. In collaboration with Dr. Paul Marcogliese at the University of Manitoba, the Simmen lab showed that glial cells of the brain no longer communicate properly with nerve cells in the brain, and thus trigger the epileptic syndrome.
While the role of TMX2 in NEDMCMS still requires further study, there is little doubt of the impact of TMX2 in regulating cellular stress. The results of this paper will increase our knowledge of the inner workings of cell biology and rare epileptic diseases, where ERMCS don’t function properly.