Journal
CELL DEATH & DISEASE
Volume 12, Issue 7, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-03979-z
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Funding
- National Institute of Neurological Disorders and Stroke [R01NS109088, R01NS100350, R01GM129034]
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The mitochondria are the main oxygen consumers in cells and are primarily affected by hypoxia. Research in C. elegans has shown that resistance to hypoxic cell death mitigates hypoxia-induced mitochondrial protein aggregation (HIMPA) and that activation of the mitochondrial unfolded protein response (UPRmt) also mitigates HIMPA. However, UPRmt activation is not necessary or sufficient for resistance to hypoxic cell death, indicating that UPRmt may protect against mitochondrial protein aggregation but not necessarily cell death in hypoxic conditions.
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.
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