[
International Worm Meeting,
2021]
Oxygen is essential for organismal function due to its role in cellular metabolism. Mitochondria are organelles that utilize substrates and oxygen to produce ATP. Dysregulation in oxygen supply caused by hypoxia, a condition of low oxygen tension, followed by the restoration of oxygen or reoxygenation, leads to mitochondrial dysfunction and reactive oxygen species (ROS) production. However, organisms have evolved various ways to sense and respond to changes in oxygen concentration. For example, C. elegans surveil their environment and respond to mitochondria distress and changes in oxygen concentration through behavioral avoidance responses but the mechanisms are unknown. Mitochondrial complex I of the electron transport chain is a major site of ROS production and is canonically associated with oxidative damage following hypoxic exposure. However, ROS also play important role in hypoxic signaling and we sought to untangle the dual role of complex I ROS in hypoxic signaling. We found that ROS is required for mediating behavioral responses to hypoxia and that ROS generated by the complex I inhibitor, rotenone, is sufficient. We then developed an optogenetic approach to spatiotemporally control complex I ROS production with light to demonstrate the role of site-specific ROS signaling. Light-induced complex I ROS rapidly and reversibly increased behavior. We showed that the bioenergetic effect of light induced complex I ROS was selective to complex I activity. Using genetic and pharmacologic approaches, we then characterized the ROS species and found that the matrix generation of H2O2 mediated the behavioral response. Surprisingly, this effect was mediated through a single thiol modification on complex I. We showed that mutants lacking the thiol residue were not responsive to acute hypoxic signaling. The hypoxic signaling mediated through the thiol extended to protection against prolong hypoxia-reoxygenation. Overall, we demonstrate that site-specific ROS can result in a pro-survival response to hypoxia through single thiol modification.