Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts.

ABSTRACT: 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, Hif1? and Hif2?. The increase of Hif1? up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2? down-regulated the expression of iron-sulfur cluster (Fe-S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration. Inhibition of Hif1? by genetic knockdown or a specific inhibitor prevented Hif1?-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2? by genetic knockdown or selective disruption of the heterodimerization of Hif2? and Hif1? 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 Hif1? and Hif2? in MEFs.

SUBMITTER: Li H 

PROVIDER: S-EPMC6525483 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature