Hypoxia-inducible Factor 2α Regulates Expression of the Mitochondrial Aconitase Chaperone Protein Frataxin

Abstract

Mice lacking؊/؊ 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-2␣ through a consensus HIF-responsive enhancer element. In summary, the studies reveal that Fxn, like Sod2, is a nuclear-encoded, mitochondrial-localized HIF-2␣ target gene required for optimal mitochondrial homeostasis. These findings expand upon the previously defined role of HIF-2␣ in the cellular response to oxidative stress and identify a novel link of HIF-2␣ with mitochondrial homeostasis.

Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc

“…Although HIF-2 expression levels remained constant, there appeared to be a significant, albeit conservative, increase in transcriptional activity under hypoxic conditions. With respect to functional activities of this HIF isoform, unlike the case in most other tissues, HIF-2 failed to increase the transcriptional activities of SOD2 and frataxin, 2 common target genes involved in radical dismutation (15,16). However, under hypoxic conditions, HIF-2 regulated the expression and promoter activity of cited2, which in turn modulated HIF-1-and HIF-2-mediated VEGF expression.…”

“…While the role of SOD2 is to promote radical dismutation, the function of frataxin in skeletal tissues is less well known, although it serves as a mitochondrial iron-binding chaperone protein in biosynthesis of heme and Fe/S clusters (16). It is likely that both these proteins are involved in maintaining mitochondrial homeostasis by counteracting increased oxidative stress (16).…”

“…While the role of SOD2 is to promote radical dismutation, the function of frataxin in skeletal tissues is less well known, although it serves as a mitochondrial iron-binding chaperone protein in biosynthesis of heme and Fe/S clusters (16). It is likely that both these proteins are involved in maintaining mitochondrial homeostasis by counteracting increased oxidative stress (16). Thus, our observation was not unexpected, since we and others have found that oxidative metabolism in nucleus pulposus cells is limited and the mitochondrial content is very low (6,25).…”

“…Recent evidence suggests that HIF-1 and HIF-2 are not redundant, and that the relative importance of each of the homologs, in response to hypoxia, varies among different cell types (14). For example, unlike HIF-1, HIF-2 regulates expression of a number of unique genes including superoxide dismutase 2 (SOD2), catalase, frataxin, Wisp2, Oct4, and cited2 (15)(16)(17)(18). Recently, it was documented that HIF-2 regulates matrix gene expression in articular chondrocytes (19,20).…”

Hypoxia Inducible Factor-2α Stabilization and Maxi-K + Channel β 1 -Subunit Gene Repression by Hypoxia in Cardiac Myocytes

“…42 Hif-2␣-dependent genes may also be critical for mitochondrial function and oxidative stress defense in adult life. 43,44 The ␤ 1 -subunit promoter contains putative hypoxic response elements, hence it is plausible that Hif-2␣ directly mediates repression of the ␤ 1 -subunit gene. However, the existence of hypoxic response element sequences does not necessarily demonstrate a Hif-mediated effect 45 ; therefore, we cannot discard the possibility that Hif-2␣ induces a repressor protein which, in turn, acts on the ␤ 1 -subunit promoter.…”