AIF: A Multifunctional Cog in the Life and Death Machine

Hansen, Tania M.; Nagley, Phillip

doi:10.1126/stke.2003.193.pe31

Cited by 17 publications

(7 citation statements)

References 12 publications

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“…These observations are consistent with the localization of the FeS cluster biogenesis machinery and key FeS protein metabolic functions in mitochondria (2,9). Moreover, because mitochondria are the primary energy providers of mammalian cells and key players in a large variety of metabolic processes (11), they have been implicated in metabolic diseases such as type II diabetes (12)(13)(14)(15).…”

supporting

confidence: 69%

NADPH Inhibits [2Fe-2S] Cluster Protein Transfer from Diabetes Drug Target MitoNEET to an Apo-acceptor Protein

Zuris

Ali

Yeh

et al. 2012

Journal of Biological Chemistry

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supporting

confidence: 69%

NADPH Inhibits [2Fe-2S] Cluster Protein Transfer from Diabetes Drug Target MitoNEET to an Apo-acceptor Protein

Zuris

Ali

Yeh

et al. 2012

Journal of Biological Chemistry

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“…These observations are consistent with the localization of the FeS cluster biogenesis machinery and key FeS protein metabolic functions in mitochondria (16,23). Moreover, as mitochondria are the primary energy providers of mammalian cells and key players in a large variety of metabolic processes (25), they have been implicated in metabolic diseases such as type II diabetes (26)(27)(28)(29).…”

supporting

confidence: 69%

Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein

Zuris

Harir

Conlan

et al. 2011

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

121

176

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MitoNEET (mNT) is an outer mitochondrial membrane target of the thiazolidinedione diabetes drugs with a unique fold and a labile [2Fe-2S] cluster. The rare 1-His and 3-Cys coordination of mNT's [2Fe-2S] leads to cluster lability that is strongly dependent on the presence of the single histidine ligand (His87). These properties of mNT are similar to known [2Fe-2S] shuttle proteins. Here we investigated whether mNT is capable of cluster transfer to acceptor protein(s). cluster transfer is observed between oxidized mNT and apo-ferredoxin (a-Fd) using UV-VIS spectroscopy and native-PAGE, as well as with a mitochondrial iron detection assay in cells. The transfer is unidirectional, proceeds to completion, and occurs with a second-order-reaction rate that is comparable to known iron-sulfur transfer proteins. Mutagenesis of His87 with Cys (H87C) inhibits transfer of the [2Fe-2S] clusters to a-Fd. This inhibition is beyond that expected from increased cluster kinetic stability, as the equivalently stable Lys55 to Glu (K55E) mutation did not inhibit transfer. The H87C mutant also failed to transfer its iron to mitochondria in HEK293 cells. The diabetes drug pioglitazone inhibits iron transfer from WT mNT to mitochondria, indicating that pioglitazone affects a specific property, [2Fe-2S] cluster transfer, in the cellular environment. This finding is interesting in light of the role of iron overload in diabetes. Our findings suggest a likely role for mNT in [2Fe-2S] and/or iron transfer to acceptor proteins and support the idea that pioglitazone's antidiabetic mode of action may, in part, be to inhibit transfer of mNT's [2Fe-2S] cluster.CISD1 | diabetes | FeS cluster | oxidative stress M itoNEET (mNT) is a newly discovered target (1) of the insulin-sensitizing thiazolidinedione (TZD) class of type II diabetes drugs (2, 3), which interact with the canonical target PPARγ (4, 5). The interaction of TZD drugs with mNT has been proposed to be of therapeutic importance (1,6). This is the first iron-sulfur protein to be directly targeted by drug binding (1, 6). The protein contains two [2Fe-2S] clusters, which have been shown to be chemically labile (7). Initial characterization of mNT's redox active and pH labile [2Fe-2S] clusters show that both properties are modulated by binding of TZDs (6,8), indicating a direct interaction of the protein with the TZD drugs. A second related member of the human NEET protein family, Miner1, is structurally homologous to mNT (9). Miner1 has recently been linked to autophagy, apoptosis, and aging (10, 11), and mis-splicing is associated with a rare disease, known as Wolfram Syndrome 2 (12). Together, mNT and Miner1 represent a new class of NEET iron-sulfur (FeS) proteins characterized structurally by their unique homodimeric fold and rare 3-Cys-1-His [2Fe-2S] cluster ligand environment (6,9,13,14).Iron-sulfur (FeS) cluster-containing proteins are key players in many essential processes, such as photosynthesis, respiration, and nitrogen fixation (15, 16). They appear in various compositions and ...

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“…9). Interestingly, both AIF and AIFL induce apoptosis (10,(22)(23)(24)(25)(26)32) (Figs. 6 -10), and both are conserved from C. elegans to humans (32) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…AIF and EndoG can cause apoptotic changes independent of caspase activity (10,12). AIF is one of the apoptogenic molecules released from mitochondria upon multiple stimuli (10,(22)(23)(24)(25)(26). Overexpression of AIF can cause apoptosis independent of caspases (10), although it was also shown that AIF overexpression was insufficient to induce apoptosis (27) and overexpression of AIF in granule cells decreased peroxide-mediated cell death (28).…”

mentioning

confidence: 99%

Molecular Cloning and Characterization of a Human AIF-like Gene with Ability to Induce Apoptosis

Xie

Lin

Zhang

et al. 2005

Journal of Biological Chemistry

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In this study, we cloned and characterized a human gene homologous to the apoptosis-inducing factor (AIF), which is named AIF-like (AIFL). Human AIFL has 598 amino acids, with a characteristic Rieske domain and a pyridine nucleotide-disulfide oxidoreductase domain (Pyr_redox). AIFL shares 35% homology with AIF, mainly in the Pyr_redox domain. Reverse transcriptase-PCR analysis showed the expression of AIFL mRNA in all tissues tested, i.e. brain, colon, heart, kidney, liver, lung, muscle, ovary, pancreas, placenta, small intestine, and testis. We developed antibodies against human AIFL using fusion proteins as antigens. The antibodies specifically recognized the antigen and heterologously expressed AIFL proteins. The expression of AIFL proteins in human tissues was also ubiquitous, demonstrated by immunohistochemistry in tissue array slides. Subcellular fractionation and immunofluorescence staining studies revealed that AIFL is predominantly localized to the mitochondria. Similar to AIF, overexpression of AIFL induced apoptosis, as shown by increased cytoplasmic nucleosomes and subdiploid cell populations in AIFLtransfected cells. The segment 1-190 containing the Rieske domain induced apoptosis, whereas the segment containing the Pyr_redox domain did not contribute to the pro-apoptotic function. The mitochondrial membrane potential of cells transfected with AIFL was significantly more depolarized than that of the control. AIFL transfection-induced cytochrome c release and cleavage of caspase 3. Furthermore, the pan-caspase inhibitor Z-VADfmk inhibited AIFL induced apoptosis. In summary, AIFL induces apoptosis in a caspase-dependent manner when heterologously expressed.

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AIF: A Multifunctional Cog in the Life and Death Machine

Cited by 17 publications

References 12 publications

NADPH Inhibits [2Fe-2S] Cluster Protein Transfer from Diabetes Drug Target MitoNEET to an Apo-acceptor Protein

NADPH Inhibits [2Fe-2S] Cluster Protein Transfer from Diabetes Drug Target MitoNEET to an Apo-acceptor Protein

Facile transfer of [2Fe-2S] clusters from the diabetes drug target mitoNEET to an apo-acceptor protein

Molecular Cloning and Characterization of a Human AIF-like Gene with Ability to Induce Apoptosis

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