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Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis

Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macropha...

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Autores principales: Fuhrmann, Dominik C., Mondorf, Antonia, Beifuß, Josefine, Jung, Michaela, Brüne, Bernhard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452134/
https://www.ncbi.nlm.nih.gov/pubmed/32810738
http://dx.doi.org/10.1016/j.redox.2020.101670
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author Fuhrmann, Dominik C.
Mondorf, Antonia
Beifuß, Josefine
Jung, Michaela
Brüne, Bernhard
author_facet Fuhrmann, Dominik C.
Mondorf, Antonia
Beifuß, Josefine
Jung, Michaela
Brüne, Bernhard
author_sort Fuhrmann, Dominik C.
collection PubMed
description Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis.
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spelling pubmed-74521342020-09-03 Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis Fuhrmann, Dominik C. Mondorf, Antonia Beifuß, Josefine Jung, Michaela Brüne, Bernhard Redox Biol Research Paper Cellular iron, at the physiological level, is essential to maintain several metabolic pathways, while an excess of free iron may cause oxidative damage and/or provoke cell death. Consequently, iron homeostasis has to be tightly controlled. Under hypoxia these regulatory mechanisms for human macrophages are not well understood. Hypoxic primary human macrophages reduced intracellular free iron and increased ferritin expression, including mitochondrial ferritin (FTMT), to store iron. In parallel, nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy, decreased and was proven to directly regulate FTMT expression. Reduced NCOA4 expression resulted from a lower rate of hypoxic NCOA4 transcription combined with a micro RNA 6862-5p-dependent degradation of NCOA4 mRNA, the latter being regulated by c-jun N-terminal kinase (JNK). Pharmacological inhibition of JNK under hypoxia increased NCOA4 and prevented FTMT induction. FTMT and ferritin heavy chain (FTH) cooperated to protect macrophages from RSL-3-induced ferroptosis under hypoxia as this form of cell death is linked to iron metabolism. In contrast, in HT1080 fibrosarcome cells, which are sensitive to ferroptosis, NCOA4 and FTMT are not regulated. Our study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis. Elsevier 2020-08-03 /pmc/articles/PMC7452134/ /pubmed/32810738 http://dx.doi.org/10.1016/j.redox.2020.101670 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
Fuhrmann, Dominik C.
Mondorf, Antonia
Beifuß, Josefine
Jung, Michaela
Brüne, Bernhard
Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
title Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
title_full Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
title_fullStr Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
title_full_unstemmed Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
title_short Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
title_sort hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452134/
https://www.ncbi.nlm.nih.gov/pubmed/32810738
http://dx.doi.org/10.1016/j.redox.2020.101670
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