Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 20, Pages 9871-9876Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1820051116
Keywords
iron regulatory protein 2; mitochondrial function; energy metabolism; hypoxia inducible factors
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Funding
- National Basic Research Program of China [2015CB856300]
- National Natural Science Foundation of China [31571218]
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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 alpha and Hif2 alpha. The increase of Hif1 alpha up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2 alpha 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 alpha by genetic knockdown or a specific inhibitor prevented Hif1 alpha-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2 alpha by genetic knockdown or selective disruption of the heterodimerization of Hif2 alpha and Hif1 beta 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 alpha and Hif2 alpha in MEFs.
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