Hypoxia inhibits ferritinophagy, increases mitochondrial ferritin, and protects from ferroptosis.
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TLDR
This study helps to understand mechanisms of hypoxic FTMT regulation and to link ferritinophagy and macrophage sensitivity to ferroptosis and in HT1080 fibrosarcome cells, NCOA4 and FTMT are not regulated.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.read more
Citations
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Journal ArticleDOI
Ferroptosis Mechanisms Involved in Neurodegenerative Diseases.
Cadiele Oliana Reichert,Fábio Alessandro de Freitas,Juliana Sampaio-Silva,Leonardo Rokita-Rosa,Priscila de Lima Barros,Debora Levy,Sérgio Paulo Bydlowski,Sérgio Paulo Bydlowski +7 more
TL;DR: The main mechanisms involved in the process of ferroptosis such as lipid peroxidation, glutathione peroxidase 4 enzyme activity, and iron metabolism are reviewed.
Journal ArticleDOI
Ferritinophagy and ferroptosis in the management of metabolic diseases.
Amir Ajoolabady,Hamid Aslkhodapasandhokmabad,Peter Libby,Jaakko Tuomilehto,Jaakko Tuomilehto,Jaakko Tuomilehto,Gregory Y.H. Lip,Josef M. Penninger,Josef M. Penninger,Des R. Richardson,Des R. Richardson,Des R. Richardson,Daolin Tang,Hao Zhou,Hao Zhou,Shuyi Wang,Shuyi Wang,Daniel J. Klionsky,Guido Kroemer,Jun Ren,Jun Ren +20 more
TL;DR: In this article, the authors delineate the role of ferritinophagy in ferroptosis, and its underlying regulatory mechanisms, to unveil the therapeutic value of the selective form of autophagy as a target in the combat of metabolic diseases.
Journal ArticleDOI
On Iron Metabolism and Its Regulation.
Anne-Cathrine S. Vogt,Tasneem Arsiwala,Mona O. Mohsen,Monique Vogel,Vania Manolova,Martin F. Bachmann +5 more
TL;DR: A review of the key mechanisms and players involved in cellular and systemic iron regulation is presented in this paper, where the peptide hormone hepcidin is used to induce internalization and degradation of the iron transporter FPN.
Journal ArticleDOI
Organelle-specific regulation of ferroptosis.
TL;DR: In this paper, the authors outline the evidence implicating different organelles (including mitochondria, lysosomes, endoplasmic reticulum, lipid droplets, peroxisomes, Golgi apparatus, and nucleus) in the ignition or avoidance of ferroptosis.
Journal ArticleDOI
Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis
TL;DR: In this paper, the role of ferroptosis in osteoporosis was investigated in vitro and in vivo, and it was shown that targeting HIF-1α and ferritin in osteoclasts could be an alternative in treatment of bone loss.
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