A mitochondrial iron-sensing pathway regulated by DELE1
A mitochondrial iron-sensing pathway regulated by DELE1
Summary 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 involves a heme-independent mechanism that 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). Moreover, depletion of the mitochondrial ABC transporter ABCB7 that is involved in iron-sulfur cluster (ISC) metabolism markedly abrogates iron deficiency-induced ISR activation, suggesting the possible involvement of ISC-related molecules in this activation. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized iron monitoring system that connects the mitochondria to the cytosol.
Jae Lucas T、Sekine Shiori、Fessler Evelyn、Houston Ryan、Narendra Derek P、Sekine Yusuke
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universit?t M¨1nchenAging Institute, Department of Medicine, School of Medicine, University of Pittsburgh||Division of Cardiology, Department of Medicine, School of Medicine, University of PittsburghGene Center and Department of Biochemistry, Ludwig-Maximilians-Universit?t M¨1nchenAging Institute, Department of Medicine, School of Medicine, University of PittsburghInherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of HealthAging Institute, Department of Medicine, School of Medicine, University of Pittsburgh||Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh
生物化学分子生物学细胞生物学
Heme-regulated inhibitor (HRI)DAP3 binding cell death enhancer 1 (DELE1)LON protease 1 (LONP1)ATP binding cassette (ABC) transporterintegrated stress response (ISR)ironiron-sulfur cluster (ISC)mitochondriamitochondrial importmitochondrial proteostasis
Jae Lucas T,Sekine Shiori,Fessler Evelyn,Houston Ryan,Narendra Derek P,Sekine Yusuke.A mitochondrial iron-sensing pathway regulated by DELE1[EB/OL].(2025-03-28)[2025-05-12].https://www.biorxiv.org/content/10.1101/2022.04.14.488327.点此复制
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