Final Report Summary - WTBLDOHRNCE (Walking the tightrope between life and death: Oxygen homeostasis regulation in the nematode Caenorhabditis elegans)
Deprivation of oxygen (Hypoxia) followed by reoxygenation can cause oxidative injuries that may lead to cell death. Indeed, oxidative damage is a major component in many pathological conditions including myocardial ischemia and stroke. For that reason, understanding how animals recover from oxidative stress is important for developing better treatments for these diseases. In the “Walking the tightrope between life and death: Oxygen homeostasis regulation in the nematode Caenorhabditis elegans” ERC grant we addressed this question through a set of integrated projects. We showed that C. elegans worms bearing an active globin 5 (GLB-5) recover remarkably fast from oxidative stress caused by a sharp transition from hypoxia to 21% O2. By monitoring the changes in neuronal and intestinal gene expression, we revealed an unexpected enrichment of innate immunity genes during oxidative stress. The connection between oxidative stress and the innate immune response is intriguing and appears to be conserved in evolution. Our results demonstrated that GLB-5 increases the resistance of worms to bacterial infection in an HIF-1 dependent fashion. Moreover, using forward genetics, we discovered conserved structural determinants in the soluble guanylate cyclases GCY-35 and GCY-36 that are crucial for the fast recovery from oxidative stress. Remarkably, our data suggest that this structural determinants are important for regulating both O2 and nitric oxide sensors. Oxidative stress caused by super physiological levels of hydrogen sulfide (H2S) can cause sever cell damage and death. We developed a new method to study H2S-defence mechanisms in C. elegans and identified mutants the significantly increase the tolerance to sulfide. We show that mitochondria, thioredoxin and HIF-1 signaling play a major role in regulating the protective mechanisms against H2S. In conclusion, our ERC grant resulted in novel and exciting results that pave the way to new hypotheses and future research in the redox and O2-biology fields.