The Diabetes Drug Target MitoNEET Governs a Novel Trafficking Pathway to Rebuild an Fe-S Cluster into Cytosolic Aconitase/Iron Regulatory Protein 1

Ferecatu, Ioana; Gonçalves, Sara; Golinelli-Cohen, Marie-Pierre; Clémancey, Martin; Martelli, Alain; Riquier, Sylvie; Guittet, Éric; Latour, Jean‐Marc; Puccio, Hélène; Drapier, Jean‐Claude; Lescop, Ewen; Bouton, Cécile

doi:10.1074/jbc.m114.548438

Cited by 103 publications

(149 citation statements)

References 76 publications

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“…Apoferredoxin-In previous studies, a role for mNT in Fe-S transfer/repair to apo-acceptors has been proposed (12,13). However, a clear distinction could not be drawn between the specific role of dioxygen in the cluster transfer reaction and the role played by the redox state of the mNT Fe-S cluster, because these studies were performed under aerobic conditions with the oxidized form of mNT and under anaerobic conditions with the reduced form.…”

Section: Role Of Dioxygen In the Transfer Of The Mnt Fe-s Tomentioning

confidence: 97%

“…Expression and Purification of mNT Proteins-Recombinant human mNT and mNT 44 -108 lacking the 32 and the 43 N-terminal amino acids, respectively, were expressed in E. coli and purified as described previously (13). Degassed buffers were used during all purification steps.…”

Section: Methodsmentioning

confidence: 99%

“…Fig. 3B presents the low-field Mössbauer spectrum of reduced 57 ] 2ϩ form (left top) (13). The spectrum of the reduced holo-mNT is similar to those of the [2Fe-2S] ϩ forms of Pseudomonas putida putidaredoxin (28), Aquifex aeolicus ferredoxin I (29) (both protein clusters are coordinated by four cysteines), E. coli IscR (30) (three cysteines and one histidine), and P. putida Rieske protein (31) (two histidines and two cysteines).…”

Section: Role Of Dioxygen In the Transfer Of The Mnt Fe-s Tomentioning

confidence: 99%

“…Spectroscopic Characterization of Reduced Holo-mNT-The oxidized form of holo-mNT, which mediates Fe-S transfer, has been well characterized in vitro (13,18,25). However, reduced holo-mNT, which is inactive as an Fe-S transfer protein, is poorly characterized.…”

Section: Role Of Dioxygen In the Transfer Of The Mnt Fe-s Tomentioning

confidence: 99%

“…mNT is also able to transfer its cluster in vitro to a cyanobacterial (12) and Escherichia coli apoferredoxin or to human ironregulatory protein-1 (IRP-1)/cytosolic aconitase (13). Recently, it has been proposed that mNT plays a specific role in cytosolic Fe-S cluster repair of IRP-1, a key regulator of cellular iron homeostasis in mammalian cells (13).…”

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confidence: 99%

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Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

Golinelli-Cohen

Lescop

Mons

et al. 2016

Journal of Biological Chemistry

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Human mitoNEET (mNT) is the first identified Fe-S protein of the mammalian outer mitochondrial membrane. Recently, mNT has been implicated in cytosolic Fe-S repair of a key regulator of cellular iron homeostasis. Here, we aimed to decipher the mechanism by which mNT triggers its Fe-S repair capacity. By using tightly controlled reactions combined with complementary spectroscopic approaches, we have determined the differential roles played by both the redox state of the mNT cluster and dioxygen in cluster transfer and protein stability. We unambiguously demonstrated that only the oxidized state of the mNT cluster triggers cluster transfer to a generic acceptor protein and that dioxygen is neither required for the cluster transfer reaction nor does it affect the transfer rate. In the absence of apo-acceptors, a large fraction of the oxidized holo-mNT form is converted back to reduced holo-mNT under low oxygen tension. Reduced holo-mNT, which holds a [2Fe-2S] ؉ with a global protein fold similar to that of the oxidized form is, by contrast, resistant in losing its cluster or in transferring it. Our findings thus demonstrate that mNT uses an iron-based redox switch mechanism to regulate the transfer of its cluster. The oxidized state is the "active state," which reacts promptly to initiate Fe-S transfer independently of dioxygen, whereas the reduced state is a "dormant form." Finally, we propose that the redox-sensing function of mNT is a key component of the cellular adaptive response to help stress-sensitive Fe-S proteins recover from oxidative injury.MitoNEET (mNT) 5 is an Fe-S protein of the mammalian outer mitochondrial membrane previously identified as a target of the type II diabetes drug pioglitazone (1). This 13-kDa protein is anchored to the outer mitochondrial membrane by its 32-amino acid N terminus with the major part of the protein, including the C-terminal [2Fe-2S] binding domain, located in the cytosol (2). In vivo, the biological activity of mNT has been linked to the regulation of iron/reactive oxygen species homeostasis in vivo (3, 4) to cell proliferation in human breast cancer (5) and to the regulation of lipid and glucose metabolism (4).Crystallographic studies of the soluble form of mNT (mNT ) revealed that the protein dimerizes and accommodates one [2Fe-2S] cluster per monomer coordinated by three cysteines (Cys-72, Cys-74, and Cys-83) and one histidine (His-87) in a CDGSH domain (6 -9). The cluster is redox-active with a midpoint redox potential of roughly 0 mV at pH 7 (10), and its lability depends on its redox state and on the pH (9, 11). mNT is also able to transfer its cluster in vitro to a cyanobacterial (12) and Escherichia coli apoferredoxin or to human ironregulatory protein-1 (IRP-1)/cytosolic aconitase (13). Recently, it has been proposed that mNT plays a specific role in cytosolic Fe-S cluster repair of IRP-1, a key regulator of cellular iron homeostasis in mammalian cells (13).It has been pointed out previously (12) that oxidation of the mNT cluster is necessary to trigger Fe-S ...

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Section: Role Of Dioxygen In the Transfer Of The Mnt Fe-s Tomentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Role Of Dioxygen In the Transfer Of The Mnt Fe-s Tomentioning

confidence: 99%

Section: Role Of Dioxygen In the Transfer Of The Mnt Fe-s Tomentioning

confidence: 99%

mentioning

confidence: 99%

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Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

Golinelli-Cohen

Lescop

Mons

et al. 2016

Journal of Biological Chemistry

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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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Intracellular Iron Utilisation

2016

Iron Metabolism

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The Diabetes Drug Target MitoNEET Governs a Novel Trafficking Pathway to Rebuild an Fe-S Cluster into Cytosolic Aconitase/Iron Regulatory Protein 1

Cited by 103 publications

References 76 publications

Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

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

Intracellular Iron Utilisation

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