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

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.