A mitochondrial iron-responsive pathway regulated by DELE1

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.