Artistic representation of a mitochondrion. Image credit: Wolfgang Stief (CC BY-NC-ND 2.0)
Most animal cells carry compartments called mitochondria. These tiny powerhouses produce the energy that fuels many life processes, but they also store important compounds and can even cause an infected or defective cell to kill itself. For a cell, keeping its mitochondria healthy is often a matter of life and death: failure to do so is linked with aging, cancer or diseases such as Alzheimer’s.
The cell uses a surveillance program called the mitochondrial unfolded protein response to assess the health of its mitochondria. If something is amiss, the cell activates specific mechanisms to fix the problem, which involves turning on specific genes in its genome.
A protein named ULP-4, which is found in the worm Caenorhabditis elegans but also in humans, participates in this process. This enzyme cuts off chemical ‘tags’ known as SUMO from proteins. Adding and removing these labels changes the place and role of a protein in the cell. However, it was still unclear how ULP-4 played a role in the mitochondrial unfolded protein response.
Here, Gao et al. show that when mitochondria are in distress, ULP-4 removes SUMO from DVE-1 and ATFS-1, two proteins that control separate arms of the mitochondrial unfolded protein response. Without SUMO tags, DVE-1 can relocate to the area in the cell where it can turn on genes that protect and repair mitochondria; meanwhile SUMO-free ATFS-1 becomes more stable and can start acting on the genome. Finally, the experiments show that removing SUMO on DVE-1 and ATFS-1 is essential to keep the worms healthy and with a long lifespan under mitochondrial stress.
The experiments by Gao et al. show that the mitochondrial unfolded protein response relies, at least in part, on SUMO tags. This knowledge opens new avenues of research, and could help fight diseases that emerge when mitochondria fail.
