Effect of the mitochondrial unfolded protein response on hypoxic death and mitochondrial protein aggregation

Mitochondria are the main oxygen consumers in cells and as such are the primary organelle affected by hypoxia. All hypoxia pathology presumably derives from the initial mitochondrial dysfunction. An early event in hypoxic pathology in C. elegans is disruption of mitochondrial proteostasis with induction of the mitochondrial unfolded protein response (UPR(mt)) and mitochondrial protein aggregation. Here in C. elegans, we screen through RNAis and mutants that confer either strong resistance to hypoxic cell death or strong induction of the UPR(mt) to determine the relationship between hypoxic cell death, UPR(mt) activation, and hypoxia-induced mitochondrial protein aggregation (HIMPA). We find that resistance to hypoxic cell death invariantly mitigated HIMPA. We also find that UPR(mt) activation invariantly mitigated HIMPA. However, UPR(mt) activation was neither necessary nor sufficient for resistance to hypoxic death and vice versa. We conclude that UPR(mt) is not necessarily hypoxia protective against cell death but does protect from mitochondrial protein aggregation, one of the early hypoxic pathologies in C. elegans.