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A mitochondrial iron-responsive pathway regulated by DELE1.

Yusuke Sekine1, Ryan Houston2, Eva-Maria Eckl3

  • 1Aging 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.

Molecular Cell
|June 16, 2023
PubMed
Summary

Iron deficiency activates the heme-regulated kinase HRI via the mitochondrial protein DELE1. DELE1 stability on the mitochondria triggers the integrated stress response, protecting cells from iron-limited death.

Keywords:
DELE1HRILONP1erythroid cellsintegrated stress responseironmitochondriamitochondrial importmitochondrial proteostasis

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Area of Science:

  • Cellular Biology
  • Mitochondrial Biology
  • Iron Metabolism

Background:

  • Heme-regulated kinase (HRI) activation is known under iron deficiency, but the mechanism is unclear.
  • Mitochondria play a crucial role in cellular iron homeostasis and stress response.

Purpose of the Study:

  • To elucidate the molecular mechanism of iron-deficiency-induced HRI activation.
  • To identify the role of mitochondrial proteins in iron sensing and stress signaling.

Main Methods:

  • Investigated the role of mitochondrial protein DELE1 in HRI activation using iron chelation and gene ablation studies.
  • Assessed DELE1 mitochondrial import and stability.
  • Analyzed the integrated stress response (ISR) activation.
  • Utilized an erythroid cell model to study cell death under iron limitation.

Main Results:

  • Iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1.
  • Mitochondrial import and stability of DELE1 are regulated by iron availability.
  • DELE1 is normally degraded by the protease LONP1 after mitochondrial import.
  • Iron chelation arrests DELE1 import, stabilizing it on the mitochondrial surface and activating the HRI-mediated ISR.
  • Ablation of the DELE1-HRI-ISR pathway increases cell death under iron limitation in erythroid cells.

Conclusions:

  • Mitochondrial import regulation of DELE1 is a key component of a novel mitochondrial iron-sensing pathway.
  • This pathway activates stress signaling (ISR) in response to iron homeostasis disruption.
  • The DELE1-HRI-ISR pathway plays a cell-protective role in iron-demanding cells.