Iron loss triggers mitophagy through induction of mitochondrial ferritin

Hara, Yuichi; Izumi, Yasukatsu; Tanaka, Atsushi; Kishi, Fumio; Lemasters, John J.; Nishina, Sohji; Sasaki, Kyo; Hino, Keisuke

doi:10.15252/embr.202050202

Cited by 83 publications

(82 citation statements)

References 56 publications

(90 reference statements)

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“…Under control conditions, NCOA4 (green) appeared in the cytosol as small, perinuclear, vesicle-like structures ( Figure 6A , left), in agreement with studies indicating that NCOA4 localizes to the Golgi apparatus 69 and/or microtubules. 70 However, upon iron repletion with FAC, CD63 (red) significantly ( P < .0001) increased compared with the control ( Figure 6A-B ).…”

Section: Resultssupporting

confidence: 88%

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

Izumi

Richardson

Dhekne

et al. 2021

Blood

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Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can be also secreted by the exosome pathway (Truman-Rosentsvit M. et al. BLOOD 131 (2018) 342-352), with serum ferritin levels classically reflecting body iron stores. Iron metabolism-associated proteins, such as ferritin, are intricately regulated by cellular iron levels via the iron responsive element (IRE)-iron regulatory protein (IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein, CD63, is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5'-untranslated region (UTR) of CD63 mRNA responsible for regulating its expression in response to increased iron. Cellular iron-loading caused a marked increase in CD63 expression and the secretion from cells of CD63 positive (i.e., CD63(+)) EVs, which were shown to contain ferritin-H (FtH) and -L (FtL). Our results demonstrate that under iron-loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63(+) EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63(+) EVs, poses significant impact for understanding the local cell-to-cell exchange of ferritin and iron.

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Section: Resultssupporting

confidence: 88%

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

Izumi

Richardson

Dhekne

et al. 2021

Blood

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“…This mechanism may partly explain why cells overexpressing mitochondrial ferritin are more sensitive to oxidative stress [36]. Recent work described the induction of FtMt by the iron chelator deferiprone, resulting in increased mitophagy [37]; however, the results were affected by the use of a commercial polyclonal anti-FtMt peptide antibody, for which there were no available data about the lack of cross-reactivity with other proteins, in particular with cytosolic ferritin. Thus, more experiments are necessary to confirm these data.…”

Section: Physiological Role Of Mitochondrial Ferritinmentioning

confidence: 99%

Mitochondrial Ferritin: Its Role in Physiological and Pathological Conditions

Levi

Ripamonti

Dardi

et al. 2021

Cells

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In 2001, a new type of human ferritin was identified by searching for homologous sequences to H-ferritin in the human genome. After the demonstration that this ferritin is located specifically in the mitochondrion, it was called mitochondrial ferritin. Studies on the properties of this new type of ferritin have been limited by its very high homology with the cytosolic H-ferritin, which is expressed at higher levels in cells. This great similarity made it difficult to obtain specific antibodies against the mitochondrial ferritin devoid of cross-reactivity with cytosolic ferritin. Thus, the knowledge of the physiological role of mitochondrial ferritin is still incomplete despite 20 years of research. In this review, we summarize the literature on mitochondrial ferritin expression regulation and its physical and biochemical properties, with particular attention paid to the differences with cytosolic ferritin and its role in physiological condition. Until now, there has been no evidence that the alteration of the mitochondrial ferritin gene is causative of any disorder; however, the identified association of the mitochondrial ferritin with some disorders is discussed.

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“…In fact, abnormal cellular iron metabolism is largely affected by mitochondrial iron dyshomeostasis, which may lead to iron overload associated side effects. In turn, an iron loss induced by iron chelator triggers mitophagy [ 157 ].…”

Section: Mitochondrial Iron Ionmentioning

confidence: 99%

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease

Wang

et al. 2021

IJMS

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Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca2+, K+, Na+, Mg2+, Zn2+ and Fe2+/Fe3+. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases.

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Iron loss triggers mitophagy through induction of mitochondrial ferritin

Cited by 83 publications

References 56 publications

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles

Mitochondrial Ferritin: Its Role in Physiological and Pathological Conditions

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease

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