mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting with Transferrin Receptor

Furihata, Takaaki; Takada, Shingo; Maékawa, Shohei; Mizushima, Wataru; Watanabe, Masashi; Takahashi, Hidehisa; Fukushima, Arata; Tsuda, Michio; Matsumoto, Junichi; Kakutani, Naoya; Yokota, Takashi; Matsushima, Shoji; Otsuka, Yutaro; Matsumoto, Masaki; Nakayama, Keiichi I.; Nio‐Kobayashi, Junko; Iwanaga, Toshihoko; Sabe, Hisataka; Hatakeyama, Susumi; Tsutsui, Hiroyuki; Kinugawa, Shintaro

doi:10.1101/330084

Cited by 7 publications

(3 citation statements)

References 41 publications

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“…In this study, we demonstrated that inhibiting mitoNEET, a mitochondrial iron regulator, has a protective effect against inflammatory responses during sepsis. MitoNEET, a mitochondrial protein, plays a key role in energy metabolism, iron regulation, and production of ROS by mitochondria [ 19 , 43 ]. Our data show that inflammatory stimuli, such as LPS, which induce mitochondrial oxidative damage, trigger production of mitoNEET mRNA and protein in various animal models of and in BMDMs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress

et al. 2022

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MitoNEET (mitochondrial protein containing Asn–Glu–Glu–Thr (NEET) sequence) is a 2Fe–2S cluster-containing integral membrane protein that resides in the mitochondrial outer membrane and participates in a redox-sensitive signaling and Fe–S cluster transfer. Thus, mitoNEET is a key regulator of mitochondrial oxidative capacity and iron homeostasis. Moreover, mitochondrial dysfunction and oxidative stress play critical roles in inflammatory diseases such as sepsis. Increased iron levels mediated by mitochondrial dysfunction lead to oxidative damage and generation of reactive oxygen species (ROS). Increasing evidence suggests that targeting mitoNEET to reverse mitochondrial dysfunction deserves further investigation. However, the role of mitoNEET in inflammatory diseases is unknown. Here, we investigated the mechanism of action and function of mitoNEET during lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Levels of mitoNEET protein increased during microbial or LPS-induced sepsis. Pharmacological inhibition of mitoNEET using mitoNEET ligand-1 (NL-1) decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in animal models of sepsis, as well as LPS-induced inflammatory responses by macrophages in vitro. Inhibition of mitoNEET using NL-1 or mitoNEET shRNA abrogated LPS-induced ROS formation and mitochondrial dysfunction. Furthermore, mitochondrial iron accumulation led to generation of LPS-induced ROS, a process blocked by NL-1 or shRNA. Taken together, these data suggest that mitoNEET could be a key therapeutic molecule that targets mitochondrial dysfunction during inflammatory diseases and sepsis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress

et al. 2022

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“…Previous studies revealed that different cell types with reduced CISD2 or CISD1 expression accumulate high levels of iron in their mitochondria and display enhanced expression of TfR and ferritin [54,58,63]. This process is also accompanied by the activation of apoptosis, autophagy, and ferroptosis [16,33,50,54,57,58,64,65].…”

Section: Discussionmentioning

confidence: 99%

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

et al. 2022

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Considered a key aging gene, CISD2, encoding CDGSH iron-sulfur domaincontaining protein 2, plays a central role in regulating calcium homeostasis, preventing mitochondrial dysfunction, and the activation of autophagy and apoptosis in different cells. Here, we show that cardiomyocytes from CISD2null mice accumulate high levels of iron and contain high levels of transferrin receptor and ferritin. Using proteomics and transmission electron microscopy, we further show that the lack of CISD2 induces several features of the aging process in young mice, but other features are not induced. Taken together, our findings suggest that CISD2 protects cardiomyocytes from overaccumulation of iron, which is common in aging hearts and can contribute to the pathogenesis of heart failure.

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“…Downregulating any one of the NEET proteins, including MiNT, leads to increased accumulation of mitochondrial labile iron (mLI) and mitochondrial reactive oxygen species (mROS), as well as to disruptions in mitochondrial function and morphology ( 12 , 14 , 17 ). Mitochondrial iron and ROS accumulation were shown to affect mitochondrial respiratory capacity ( 12 , 18 – 26 ). Since mitochondria are considered to play a central role in bioenergetics, metabolism, and other cellular pathways ( 27 ), mitochondria morphodynamics are tightly linked to the overall bioenergetic function of cells ( 28 ).…”

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confidence: 99%

A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics

Marjault

Bai

Roy

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial inner NEET (MiNT) and the outer mitochondrial membrane (OMM) mitoNEET (mNT) proteins belong to the NEET protein family. This family plays a key role in mitochondrial labile iron and reactive oxygen species (ROS) homeostasis. NEET proteins contain labile [2Fe-2S] clusters which can be transferred to apo-acceptor proteins. In eukaryotes, the biogenesis of [2Fe-2S] clusters occurs within the mitochondria by the iron–sulfur cluster (ISC) system; the clusters are then transferred to [2Fe-2S] proteins within the mitochondria or exported to cytosolic proteins and the cytosolic iron–sulfur cluster assembly (CIA) system. The last step of export of the [2Fe-2S] is not yet fully characterized. Here we show that MiNT interacts with voltage-dependent anion channel 1 (VDAC1), a major OMM protein that connects the intermembrane space with the cytosol and participates in regulating the levels of different ions including mitochondrial labile iron (mLI). We further show that VDAC1 is mediating the interaction between MiNT and mNT, in which MiNT transfers its [2Fe-2S] clusters from inside the mitochondria to mNT that is facing the cytosol. This MiNT–VDAC1–mNT interaction is shown both experimentally and by computational calculations. Additionally, we show that modifying MiNT expression in breast cancer cells affects the dynamics of mitochondrial structure and morphology, mitochondrial function, and breast cancer tumor growth. Our findings reveal a pathway for the transfer of [2Fe-2S] clusters, which are assembled inside the mitochondria, to the cytosol.

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mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting with Transferrin Receptor

Cited by 7 publications

References 41 publications

Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress

Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress

The [2Fe‐2S] protein CISD2 plays a key role in preventing iron accumulation in cardiomyocytes

A VDAC1-mediated NEET protein chain transfers [2Fe-2S] clusters between the mitochondria and the cytosol and impacts mitochondrial dynamics

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