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A mitochondrial iron-sensing pathway regulated by DELE1

View ORCID ProfileYusuke Sekine, Ryan Houston, Evelyn Fessler, Lucas T Jae, Derek P Narendra, Shiori Sekine
doi: https://doi.org/10.1101/2022.04.14.488327
Yusuke Sekine
1Aging Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
2Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Ryan Houston
1Aging Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Evelyn Fessler
3Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
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Lucas T Jae
3Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
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Derek P Narendra
4Inherited Movement Disorders Unit, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
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Shiori Sekine
1Aging Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
5Division of Cardiology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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  • For correspondence: sekine@pitt.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# Co-first authors

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 14, 2022.
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A mitochondrial iron-sensing pathway regulated by DELE1
Yusuke Sekine, Ryan Houston, Evelyn Fessler, Lucas T Jae, Derek P Narendra, Shiori Sekine
bioRxiv 2022.04.14.488327; doi: https://doi.org/10.1101/2022.04.14.488327
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A mitochondrial iron-sensing pathway regulated by DELE1
Yusuke Sekine, Ryan Houston, Evelyn Fessler, Lucas T Jae, Derek P Narendra, Shiori Sekine
bioRxiv 2022.04.14.488327; doi: https://doi.org/10.1101/2022.04.14.488327

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