2. Academic Validation
  3. A mitochondrial iron-responsive pathway regulated by DELE1

A mitochondrial iron-responsive pathway regulated by DELE1

  • Mol Cell. 2023 Jun 15;83(12):2059-2076.e6. doi: 10.1016/j.molcel.2023.05.031.
Yusuke Sekine 1,  Ryan Houston 2,  Eva-Maria Eckl 3,  Evelyn Fessler 3,  Derek P Narendra 4,  Lucas T Jae 3,  Shiori Sekine 5
Affiliations

Affiliations

  • 1 Aging Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 2 Aging Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
  • 3 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
  • 4 Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA.
  • 5 Aging Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA; Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: sekine@pitt.edu.
PMID: 37327776 DOI: 10.1016/j.molcel.2023.05.031
Abstract

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.

Keywords

DELE1; HRI; LONP1; erythroid cells; integrated stress response; iron; mitochondria; mitochondrial import; mitochondrial proteostasis.

Figures
Products