Defining a Novel Role for Hypoxia Inducible Factor-2 Alpha (HIF-2a)/EPAS1 : Maintenance of Mitochondrial and Redox Homeostasis
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The Epas1 gene encodes HIF-2alpha , a member of the Hypoxia Inducible Factor family of transcriptional regulators. The biological role for HIF-2alpha has been elusive due to embryonic lethality of the initial Epas1-/- mouse strains. Our lab reported the generation of the first viable Epas1-/- mice using a genetic breeding strategy. Adult Epas1-/- mice exhibit gross, histological, biochemical, and molecular evidence consistent with mitochondrial dysfunction. Similarities between Epas1 and Sod2 deficient strains suggest a biochemical etiology, increased oxidative stress, as well as a molecular etiology, decreased Sod2 gene expression, for the mitochondrial dysfunction in Epas1-/- mice. Consistent with this hypothesis, Sod2 gene expression is reduced in Epas1-/- mice whereas HIF-2a induces Sod2 gene promoter in transient transfection studies. Further studies revealed impaired mitochondrial respiration, sensitized mitochondrial permeability transition pore opening, increased electron transport chain activity and reduced mitochondrial aconitase activity. Given that it is the most sensitive enzymatic marker for oxidative stress, aconitase inhibition may explain impaired respiration. Also, redox balance in Epas1-/- liver is disturbed: the reduced cytoplasmic environment, and a relative oxidized environment for mitochondria from Epas1-/- liver implies a role for HIF-2a in maintenance of cellular redox balance. All these data suggest that HIF-2a is essential for maintenance of mitochondrial function, reactive oxygen species detoxification, and redox balance.