The neurodegeneration and anemia of Irp2-/- mice and the polycythemia and pulmonary hypertension of Irp1-/- mice underline the essential role of IRP/IRE machinery in regulating cellular and systemic iron homeostasis, and also suggest that mutations of IRP1 and IRP2 could underlie some human diseases. Here, ACO1 is linked to pulmonary hypertension.