The glyoxylate shunt protein ICL-1 protects from mitochondrial superoxide stress through activation of the mitochondrial unfolded protein response.
Eliminating mitochondrial superoxide dismutase (SOD) causes neonatal lethality in mice and death of flies within 24 hours after eclosion. Deletion of mitochondrial sod genes in C. elegans impairs fertility as well, but surprisingly is not detrimental to survival of progeny generated. The comparison of metabolic pathways among mouse, flies and nematodes reveals that mice and flies lack the glyoxylate shunt. Here we show that ICL-1, the only protein of the glyoxylate shunt, is critical for protection against embryonic lethality resulting from elevated levels of mitochondrial superoxide. In exploring the mechanism by which ICL-1 protects against ROS-mediated embryonic lethality, we find that ICL-1 is required for the efficient activation of mitochondrial unfolded protein response (UPRmt) and that the UPRmt is essential to suppress embryonic/neonatal lethality in animals lacking mitochondrial SOD. In sum, we identified a biochemical pathway that highlights a molecular strategy for combating superoxide consequences in cells.