Abstract
Animals have evolved responses to low oxygen conditions to ensure their survival. Here, we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial sugar metabolism enzyme. PQM-1 promotes hypoxic fat metabolism by maintaining the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity positively regulates fat transport to developing oocytes through vitellogenins under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.
Highlights
Animals have evolved responses to low oxygen conditions to ensure their survival
We previously identified the C2H2-type zinc finger protein PQM-1 as an IIS-regulated DAF-16 antagonist and transcriptional regulator that is required for the exceptional longevity of daf-2 mutants[15]
We previously found that the zinc finger transcription factor PQM-1 is partially required for daf-2 mutants’ extended longevity[15], and we expected PQM-1 to be required for daf-2’s extended survival in hypoxic conditions
Summary
We have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. A constant oxygen supply is essential to sustain the life of aerobic organisms, which have evolved multiple adaptive mechanisms to maintain the delicate balance between oxygen supply and demand Impairment of this balance is associated with many age-related diseases, affecting pulmonary and cardiac function[1] and increasing the economic burden of aging populations in modern societies. The key hypoxic transcriptional regulator HIF-1 is required for development and survival of C. elegans at 0.5–1% oxygen (hypoxia), whereas it is not essential for survival in complete anoxia[7]. To understand the underlying mechanisms of this protection, we studied the transcriptional changes in pqm-1 mutants under normoxia versus hypoxia, and discovered that alterations in carbohydrate and lipid metabolism are key to this survival. The loss of pqm-1 under hypoxic stress is detrimental to future generations, suggesting that PQM-1 is an important component of multigenerational hypoxic survival through its regulation of key lipid metabolic genes
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