The role of novel modifications regulating superoxide dismutase-1 activity in mammalian cells: lessons from the blind mole rat

The subterranean blind mole rats (Spalax) are wild solitary mammals that live underground; and are remarkably long-lived rodents (20 years) relative to their body mass. Spalax spend most of their life in underground habitats facing hypoxic stress; however, they have evolved strategies that allow survival and intense digging activities in an environment with sharp fluctuations in oxygen. These conditions induce oxidative stress and the formation of reactive oxygen species (ROS), thus challenging homeostasis. To prevent free radical toxicity in biological systems, several enzymatic and nonenzymatic factors are involved in regulating the production and detoxification of ROS. Among the first-line defense systems against ROS are the superoxide dismutases (SODs). SOD1 is the dimeric cytosolic copper zinc superoxide dismutase and, notably, it has been shown to perform additional, non-enzymatic functions beyond dismutating superoxide radical. In the current work, we unexpectedly detected low activity of SOD1 in Spalax normal cells, accompanied by lower molecular weight (MW) when compared to other mammalian cells and to Spalax fibrosarcoma cancer cells generated in our lab, which harbor an enzymatically active wild-type SOD1. These results imply a possible novel activating post-translational modification/s existing in other mammalian cells, as well as in Spalax cancer cells, but missing in Spalax normal cells. In addition, the active form of high molecular weight existing in Spalax fibrosarcoma cells indicates a possible "switch" to turn-on SOD1 activity under yet unexplored conditions. The nature of these possible modifications in SOD1, activation mechanisms, and non-enzymatic functions are in the focus of our study.