A mitochondrial iron-responsive pathway regulated by DELE1

The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.

Automated summary

In this study, the researchers found that the activation of heme-regulated kinase HRI under iron-deficient conditions requires the involvement of mitochondrial protein DELE1. The import and stability of DELE1 in the mitochondria is regulated by iron availability. Importantly, when iron is chelated, DELE1 import is inhibited, leading to its stabilization on the mitochondrial surface and activation of the HRI-mediated integrated stress response. This study also revealed that the DELE1-HRI-ISR pathway plays a protective role in iron-demanding cell lineages.