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. [Display omitted] •Under steady state, DELE1 is degraded by matrix-resident LONP1 soon after import•DELE1 import is arrested in iron deficiency, which stabilizes it on mitochondria•The stabilized DELE1 full-length form activates HRI at the mitochondrial surface•DELE1-HRI-ISR protects erythroid cells from iron deficiency-induced cell death Sekine and Houston et al. identified DELE1 as an iron-responsive molecule at mitochondria that has cell-protective roles via HRI-ISR pathway activation in iron-deficient conditions. The mitochondrial import and subsequent degradation of DELE1 were regulated by intracellular iron availability, demonstrating the general importance of import coupled-stress sensing mechanisms at mitochondria.