TY  - JOUR
A1  - Fuhrmann, Dominik Christian
A1  - Mondorf, Antonia Maria
A1  - Beifuß, Josefine
A1  - Jung, Michaela
A1  - Brüne, Bernhard
T1  - Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis
T2  - Redox biology
N2  - Highlights
• Hypoxia decreases NCOA4 transcription in primary human macrophages.
• NCOA4 mRNA is a target of miR-6862-5p.
• Lowering NCOA4 increases FTMT abundance under hypoxia.
• FTMT and FTH protect from ferroptosis.
• Tumor cells lack the hypoxic decrease of NCOA4 and fail to stabilize FTMT.
Abstract
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.
KW  - Macrophages
KW  - Iron
KW  - Hypoxia
KW  - FTMT
KW  - NCOA4
KW  - Ferritinophagy
KW  - Ferroptosis
KW  - miR-6862-5p
KW  - JNK
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/77688
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-776880
SN  - 2213-2317
VL  - 36
IS  - 101670
PB  - Elsevier
CY  - Amsterdam
ER  -