IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies
Wen Gu, Nicole Wilkinson, Carine Fillebeen, Darren M. Blackburn, Korin Sahinyan, Eric Bonneil, Tao Zhao, Zhi Luo, Vahab D. Soleimani, Vincent Richard, Christoph H. Borchers, Albert Koulman, Benjamin Jenkins, Bernhard Michalke, Hans Zischka, Judith Sailer, Vivek Venkataramani, Othon Iliopoulos, Gary Sweeney, Kostas Pantopoulos
Wen Gu, Nicole Wilkinson, Carine Fillebeen, Darren M. Blackburn, Korin Sahinyan, Eric Bonneil, Tao Zhao, Zhi Luo, Vahab D. Soleimani, Vincent Richard, Christoph H. Borchers, Albert Koulman, Benjamin Jenkins, Bernhard Michalke, Hans Zischka, Judith Sailer, Vivek Venkataramani, Othon Iliopoulos, Gary Sweeney, Kostas Pantopoulos
View: Text | PDF
Research Article Hepatology Metabolism

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies

Abstract

Iron regulatory protein 1 (IRP1) is a posttranscriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of HIF2α mRNA, which increases renal erythropoietin production. Here, we show that Irp1–/– mice develop fasting hypoglycemia and are protected against high-fat diet–induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1–/– livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscles, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

Authors

Wen Gu, Nicole Wilkinson, Carine Fillebeen, Darren M. Blackburn, Korin Sahinyan, Eric Bonneil, Tao Zhao, Zhi Luo, Vahab D. Soleimani, Vincent Richard, Christoph H. Borchers, Albert Koulman, Benjamin Jenkins, Bernhard Michalke, Hans Zischka, Judith Sailer, Vivek Venkataramani, Othon Iliopoulos, Gary Sweeney, Kostas Pantopoulos

×

Figure 7

IRP1 deficiency stimulates insulin signaling.

Options: View larger image (or click on image) Download as PowerPoint
IRP1 deficiency stimulates insulin signaling. (A) Western blot analysis ...
(A) Western blot analysis of phospho-Akt, Akt, IRP1, and β-actin in primary hepatocytes from Irp1–/– and WT mice either left untreated or previously treated with 10 nM insulin for 5 minutes. (B) Western blot analysis of phospho-Akt, Akt, IRP1, and β-actin in primary hepatocytes from Irp1–/– and WT mice pretreated for 24 hours with 0.4 mM palmitate (conjugated to BSA) or not, and then treated with 10 nM insulin for 5 minutes. (C) Western blot analysis of phospho-Akt, Akt, IRP1, and β-actin in skeletal muscle fibers from Irp1–/– and WT mice pretreated for 24 hours with 0.4 mM palmitate (conjugated to BSA) or not, and then treated with 50 nM insulin for 20 minutes. (D) Male Irp1–/– and WT mice on high-fat diet (HFD) for 10 weeks were injected with 4U/kg insulin or not. After 5 minutes, the mice were euthanized, and skeletal muscles were analyzed by Western blotting for expression of phospho-Akt, Akt, IRP1, and β-actin. (E) A model highlighting metabolic implications of IRP1 deficiency. In A–D, all Western blots show representative samples from each condition. Phospho-Akt to Akt ratios were quantified by densitometry and plotted on the right of each Western blot. Quantitative data are presented as mean ± SEM. Statistical analysis was performed with 2-way ANOVA with Tukey’s multiple-comparison test; comparisons between 2 groups with 2-tailed Student’s t test. *P < 0.05.