Abstract
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 (UPRmt) 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 UPRmt to determine the relationship between hypoxic cell death, UPRmt activation, and hypoxia-induced mitochondrial protein aggregation (HIMPA). We find that resistance to hypoxic cell death invariantly mitigated HIMPA. We also find that UPRmt activation invariantly mitigated HIMPA. However, UPRmt activation was neither necessary nor sufficient for resistance to hypoxic death and vice versa. We conclude that UPRmt is not necessarily hypoxia protective against cell death but does protect from mitochondrial protein aggregation, one of the early hypoxic pathologies in C. elegans.
Highlights
Hypoxia, when extreme, will kill aerobic cells
We make use of hypoxia resistance (Fig. 1I). These results suggest that while resistance to hypoxic cell death and hypoxiainduced mitochondrial protein aggregation (HIMPA) may be mechanistically associated and that a functional UPRmt may be critical for aggregate formation, the UPRmt is not required for protection from hypoxia and in general activation of the UPRmt does not appear to commonly the wide variety of C. elegans RNAis and mutants that have been shown to be hypoxia protective, or to induce the UPRmt to address three fundamental questions about the relationship between mitochondrial proteostasis and hypoxic injury
Likecomponent of the mechanism underlying hypoxia resistance of wise, doxycycline and meclocycline reduced HIMPA and did not these RNAis, we screened through all the hypoxia resistance phenotype (HypR) RNAis that we could recover from the library and confirm their identity by sequence
Summary
Hypoxia, when extreme, will kill aerobic cells. The pathways whereby cells go from healthy to dead when they encounter hypoxia are many and complex. By the time cells are dying from hypoxia, virtually every energy dependent process in the cell is dysfunctional. Pathological processes that occur early in hypoxic exposure when the pathology may still be reversible are of particular interest. This pathologic time course certainly varies by cell type and organism. Central nervous system neurons and cardiac myocytes are exquisitely sensitive to hypoxia, and during complete ischemia begin dying in only a few minutes after dissolved oxygen is depleted [1, 2]. The primary cellular determinants of this enormous range in hypoxia tolerance are not well defined
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