Ferritin is regulated by a neuro-intestinal axis in the nematode Caenorhabditis elegans

Leonor Romero-Afrima; Veronica Zelmanovich; Zohar Abergel; Binyamin Zuckerman; Maayan Shaked; Rachel Abergel; Leonid Livshits; Yoav Smith; Einav Gross

doi:10.1016/j.redox.2019.101359

Ferritin is regulated by a neuro-intestinal axis in the nematode Caenorhabditis elegans

Leonor Romero-Afrima, Veronica Zelmanovich, Zohar Abergel, Binyamin Zuckerman, Maayan Shaked, Rachel Abergel, Leonid Livshits, Yoav Smith, Einav Gross^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Iron is vital for the life of most organisms. However, when dysregulated, iron can catalyze the formation of oxygen (O₂) radicals that can destroy any biological molecule and thus lead to oxidative injury and death. Therefore, iron metabolism must be tightly regulated at all times, as well as coordinated with the metabolism of O₂. However, how is this achieved at the whole animal level is not well understood. Here, we explore this question using the nematode Caenorhabditis elegans. Exposure of worms to O₂ starvation conditions (i.e. hypoxia) induces a major upregulation in levels of the conserved iron-cage protein ferritin 1 (ftn-1) in the intestine, while exposure to 21% O₂ decreases ftn-1 level. This O₂-dependent inhibition is mediated by O₂-sensing neurons that communicate with the intestine through neurotransmitter and neuropeptide signalling, and requires the activity of hydroxylated HIF-1. By contrast, the induction of ftn-1 in hypoxia appears to be HIF-1-independent. This upregulation provides protection against Pseudomonas aeruginosa bacteria and oxidative injury. Taken together, our studies uncover a neuro-intestine axis that coordinates O₂ and iron responses at the whole animal level.

Original language	American English
Article number	101359
Journal	Redox Biology
Volume	28
DOIs	https://doi.org/10.1016/j.redox.2019.101359
State	Published - Jan 2020

Bibliographical note

Funding Information:
We thank Gillian Kay for critical reading of the manuscript and the Gross laboratory members for comments and advice. We thank Prof. Millet Treinin for providing the cha-1(p1152) strain. Some strains were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs ( P40 OD010440 ). This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 989/19 ), the Israel Cancer Association , grant # 20190024 , and the European Research Council under the European Union's Seventh Framework Programme ( FP/2007–2013 )/ ERC Grant Agreement no. 281844 .

Funding Information:
We thank Gillian Kay for critical reading of the manuscript and the Gross laboratory members for comments and advice. We thank Prof. Millet Treinin for providing the cha-1(p1152) strain. Some strains were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 989/19), the Israel Cancer Association, grant # 20190024, and the European Research Council under the European Union's Seventh Framework Programme (FP/2007?2013)/ERC Grant Agreement no. 281844.

Publisher Copyright:
© 2019 The Authors

Keywords

Caenorhabditis elegans
EGL-9
Ferritin
HIF-1
Hypoxia
Oxygen sensing neurons
Soluble guanylate cyclases
VHL-1
ftn-1

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10.1016/j.redox.2019.101359

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@article{fe8aba817a2948dcb46fdbbe45bfb3ee,

title = "Ferritin is regulated by a neuro-intestinal axis in the nematode Caenorhabditis elegans",

abstract = "Iron is vital for the life of most organisms. However, when dysregulated, iron can catalyze the formation of oxygen (O2) radicals that can destroy any biological molecule and thus lead to oxidative injury and death. Therefore, iron metabolism must be tightly regulated at all times, as well as coordinated with the metabolism of O2. However, how is this achieved at the whole animal level is not well understood. Here, we explore this question using the nematode Caenorhabditis elegans. Exposure of worms to O2 starvation conditions (i.e. hypoxia) induces a major upregulation in levels of the conserved iron-cage protein ferritin 1 (ftn-1) in the intestine, while exposure to 21% O2 decreases ftn-1 level. This O2-dependent inhibition is mediated by O2-sensing neurons that communicate with the intestine through neurotransmitter and neuropeptide signalling, and requires the activity of hydroxylated HIF-1. By contrast, the induction of ftn-1 in hypoxia appears to be HIF-1-independent. This upregulation provides protection against Pseudomonas aeruginosa bacteria and oxidative injury. Taken together, our studies uncover a neuro-intestine axis that coordinates O2 and iron responses at the whole animal level.",

keywords = "Caenorhabditis elegans, EGL-9, Ferritin, HIF-1, Hypoxia, Oxygen sensing neurons, Soluble guanylate cyclases, VHL-1, ftn-1",

author = "Leonor Romero-Afrima and Veronica Zelmanovich and Zohar Abergel and Binyamin Zuckerman and Maayan Shaked and Rachel Abergel and Leonid Livshits and Yoav Smith and Einav Gross",

note = "Funding Information: We thank Gillian Kay for critical reading of the manuscript and the Gross laboratory members for comments and advice. We thank Prof. Millet Treinin for providing the cha-1(p1152) strain. Some strains were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs ( P40 OD010440 ). This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 989/19 ), the Israel Cancer Association , grant # 20190024 , and the European Research Council under the European Union's Seventh Framework Programme ( FP/2007–2013 )/ ERC Grant Agreement no. 281844 . Funding Information: We thank Gillian Kay for critical reading of the manuscript and the Gross laboratory members for comments and advice. We thank Prof. Millet Treinin for providing the cha-1(p1152) strain. Some strains were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 989/19), the Israel Cancer Association, grant # 20190024, and the European Research Council under the European Union's Seventh Framework Programme (FP/2007?2013)/ERC Grant Agreement no. 281844. Publisher Copyright: {\textcopyright} 2019 The Authors",

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doi = "10.1016/j.redox.2019.101359",

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volume = "28",

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AU - Romero-Afrima, Leonor

AU - Zelmanovich, Veronica

AU - Abergel, Zohar

AU - Zuckerman, Binyamin

AU - Shaked, Maayan

AU - Abergel, Rachel

AU - Livshits, Leonid

AU - Smith, Yoav

AU - Gross, Einav

N1 - Funding Information: We thank Gillian Kay for critical reading of the manuscript and the Gross laboratory members for comments and advice. We thank Prof. Millet Treinin for providing the cha-1(p1152) strain. Some strains were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs ( P40 OD010440 ). This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 989/19 ), the Israel Cancer Association , grant # 20190024 , and the European Research Council under the European Union's Seventh Framework Programme ( FP/2007–2013 )/ ERC Grant Agreement no. 281844 . Funding Information: We thank Gillian Kay for critical reading of the manuscript and the Gross laboratory members for comments and advice. We thank Prof. Millet Treinin for providing the cha-1(p1152) strain. Some strains were provided by the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440). This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 989/19), the Israel Cancer Association, grant # 20190024, and the European Research Council under the European Union's Seventh Framework Programme (FP/2007?2013)/ERC Grant Agreement no. 281844. Publisher Copyright: © 2019 The Authors

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N2 - Iron is vital for the life of most organisms. However, when dysregulated, iron can catalyze the formation of oxygen (O2) radicals that can destroy any biological molecule and thus lead to oxidative injury and death. Therefore, iron metabolism must be tightly regulated at all times, as well as coordinated with the metabolism of O2. However, how is this achieved at the whole animal level is not well understood. Here, we explore this question using the nematode Caenorhabditis elegans. Exposure of worms to O2 starvation conditions (i.e. hypoxia) induces a major upregulation in levels of the conserved iron-cage protein ferritin 1 (ftn-1) in the intestine, while exposure to 21% O2 decreases ftn-1 level. This O2-dependent inhibition is mediated by O2-sensing neurons that communicate with the intestine through neurotransmitter and neuropeptide signalling, and requires the activity of hydroxylated HIF-1. By contrast, the induction of ftn-1 in hypoxia appears to be HIF-1-independent. This upregulation provides protection against Pseudomonas aeruginosa bacteria and oxidative injury. Taken together, our studies uncover a neuro-intestine axis that coordinates O2 and iron responses at the whole animal level.

AB - Iron is vital for the life of most organisms. However, when dysregulated, iron can catalyze the formation of oxygen (O2) radicals that can destroy any biological molecule and thus lead to oxidative injury and death. Therefore, iron metabolism must be tightly regulated at all times, as well as coordinated with the metabolism of O2. However, how is this achieved at the whole animal level is not well understood. Here, we explore this question using the nematode Caenorhabditis elegans. Exposure of worms to O2 starvation conditions (i.e. hypoxia) induces a major upregulation in levels of the conserved iron-cage protein ferritin 1 (ftn-1) in the intestine, while exposure to 21% O2 decreases ftn-1 level. This O2-dependent inhibition is mediated by O2-sensing neurons that communicate with the intestine through neurotransmitter and neuropeptide signalling, and requires the activity of hydroxylated HIF-1. By contrast, the induction of ftn-1 in hypoxia appears to be HIF-1-independent. This upregulation provides protection against Pseudomonas aeruginosa bacteria and oxidative injury. Taken together, our studies uncover a neuro-intestine axis that coordinates O2 and iron responses at the whole animal level.

KW - Caenorhabditis elegans

KW - EGL-9

KW - Ferritin

KW - HIF-1

KW - Hypoxia

KW - Oxygen sensing neurons

KW - Soluble guanylate cyclases

KW - VHL-1

KW - ftn-1

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DO - 10.1016/j.redox.2019.101359

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AN - SCOPUS:85074116206

SN - 2213-2317

VL - 28

JO - Redox Biology

JF - Redox Biology

M1 - 101359

ER -

Ferritin is regulated by a neuro-intestinal axis in the nematode Caenorhabditis elegans

Abstract

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Keywords

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