# IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies

## TL;DR

Mice lacking IRP1 show altered energy metabolism and are protected against metabolic syndrome pathologies.

## Contribution

IRP1 deficiency is shown to alter mitochondrial metabolism and protect against metabolic syndrome.

## Key findings

- Irp1–/– mice develop fasting hypoglycemia and resist high-fat diet–induced hyperglycemia and hepatic steatosis.
- IRP1 deficiency causes mitochondrial dysfunction and a shift to glycolytic ATP production.
- Altered redox balance in IRP1-deficient mice leads to metabolic rewiring and increased insulin sensitivity.

## 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.

Mice lacking iron regulatory protein 1 (IRP1) show altered energy metabolism and are protected against metabolic syndrome pathologies