Hypoxia-inducible factor 2α regulates expression of the mitochondrial aconitase chaperone protein frataxin

Yavuz Oktay, Elhadji Dioum, Satoshi Matsuzaki, Kan Ding, Liang Jun Yan, Ronald G. Haller, Luke I. Szweda, Joseph A. Garcia

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63 Scopus citations

Abstract

Mice lacking Epas1, encoding the transcription factor Hypoxia-inducible Factor 2α (HIF-2α), exhibit an apparent mitochondrial disease state. Similarities between knock-outs of Epas1 and of Sod2, encoding the mitochondrial antioxidant enzyme manganese superoxide dismutase, led to the identification of Sod2 as a HIF-2α target gene. However, Sod2 levels in Epas1-/- liver are intermediate between that of Sod+/- and Sod2-/- mice, which have subtle or severe phenotypes, respectively. This suggests that additional HIF-2α target genes besides Sod2 contribute to the Epas1-/- mitochondrial disease state. To define the nature of the mitochondrial defect in Epas1-/- liver, we performed biophysical, biochemical, and molecular studies. In the setting of decreased Sod2 levels and increased oxidative stress, we found reduced respiration, sensitized mitochondrial permeability transition pore opening, intact electron transport chain activities, and impaired mitochondrial aconitase activity. Mitochondrial aconitase protein levels were preserved, whereas mRNA and protein levels for frataxin, the oxidative stress-regulated mitochondrial aconitase chaperone protein, were markedly reduced in Epas1-/- livers. The mouse Fxn promoter was preferentially activated by HIF-2α through a consensus HIF-responsive enhancer element. In summary, the studies reveal that Fxn, like Sod2, is a nuclear-encoded, mitochondrial-localized HIF-2α target gene required for optimal mitochondrial homeostasis. These findings expand upon the previously defined role of HIF-2α in the cellular response to oxidative stress and identify a novel link of HIF-2α with mitochondrial homeostasis.

Original languageEnglish
Pages (from-to)11750-11756
Number of pages7
JournalJournal of Biological Chemistry
Volume282
Issue number16
DOIs
StatePublished - 20 Apr 2007

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    Oktay, Y., Dioum, E., Matsuzaki, S., Ding, K., Yan, L. J., Haller, R. G., Szweda, L. I., & Garcia, J. A. (2007). Hypoxia-inducible factor 2α regulates expression of the mitochondrial aconitase chaperone protein frataxin. Journal of Biological Chemistry, 282(16), 11750-11756. https://doi.org/10.1074/jbc.M611133200