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广东快乐十分排除一码:Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts
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Iron regulatory proteins (IRPs) control cellular iron homeostasis. Irp2 knockout mice show symptoms of neurological disorders, which are considered to result from impaired mitochondrial activity. To explore the involvement of Irp2 in mitochondrial function, we examined the metabolic pathways of Irp2-depleted mouse embryonic fibroblasts. We found that Irp2 deficiency switches cellular metabolic pathways from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. We further revealed that Irp2 deficiency induces the expression of Hif1α and Hif2α; Hif1α enhances aerobic glycolysis by upregulating its target genes related to the glycolytic pathway, and Hif2α suppresses mitochondrial Fe–S biosynthesis and OXPHOS. This identified mechanism implies that high-energy-need tissues, such as the central nervous system, could be affected when Irp2 is deficient, leading to neurological disorders.
The importance of the role of iron regulatory proteins (IRPs) in mitochondrial iron homeostasis and function has been raised. To understand how an IRP affects mitochondrial function, we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α. The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron–sulfur cluster (Fe–S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration. Inhibition of Hif1α by genetic knockdown or a specific inhibitor prevented Hif1α-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2α by genetic knockdown or selective disruption of the heterodimerization of Hif2α and Hif1β restored the mitochondrial ETC and coupled oxidative phosphorylation (OXPHOS) by enhancing Fe–S biogenesis and increasing ETC-related gene expression. Our results indicate that Irp2 modulates the metabolic switch from aerobic glycolysis to OXPHOS that is mediated by Hif1α and Hif2α in MEFs.
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Author contributions: H.L. and K.L. designed research; H.L., Y.L., L.S., J.C., J.W., W.Z., X.P., and W.D. performed research; T.Q. and K.L. contributed new reagents/analytic tools; H.L., T.Q., and K.L. analyzed data; and H.L. and K.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1820051116/-/DCSupplemental.
Published under the PNAS license.