title: Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical properties of a novel cellular target for anti-diabetic drugs.
abstract: Nutrient-deprivation autophagy factor-1 (NAF-1) (synonyms: Cisd2, Eris, Miner1, and Noxp70) is a [2Fe-2S] cluster protein immune-detected both in endoplasmic reticulum (ER) and mitochondrial outer membrane. It was implicated in human pathology (Wolfram Syndrome 2) and in BCL-2 mediated antagonization of Beclin 1-dependent autophagy and depression of ER calcium stores. To gain insights about NAF-1 functions, we investigated the biochemical properties of its 2Fe-2S cluster and sensitivity of those properties to small molecules. The structure of the soluble domain of NAF-1 shows that it forms a homodimer with each protomer containing a [2Fe-2S] cluster bound by 3 Cys and one His. NAF-1 has shown the unusual abilities to transfer its 2Fe-2S cluster to an apo-acceptor protein (followed in vitro by spectrophotometry and by native PAGE electrophoresis) and to transfer iron to intact mitochondria in cell models (monitored by fluorescence imaging with iron fluorescent sensors targeted to mitochondria). Importantly, the drug pioglitazone abrogates NAF-1's ability to transfer the cluster to acceptor proteins and iron to mitochondria. Similar effects were found for the anti-diabetes and longevity-promoting antioxidant resveratrol. These results reveal NAF-1 as a previously unidentified cell target of anti-diabetes thiazolidinedione drugs like pioglitazone and of the natural product resveratrol, both of which interact with the protein and stabilize its labile [2Fe-2S] cluster.
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Tamir
authors.forename: John A
authors.initials: JA
authors.lastname: Zuris
authors.forename: Lily
authors.initials: L
authors.lastname: Agranat
authors.forename: Colin H
authors.initials: CH
authors.lastname: Lipper
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Conlan
authors.forename: Dorit
authors.initials: D
authors.lastname: Michaeli
authors.forename: Yael
authors.initials: Y
authors.lastname: Harir
authors.forename: Mark L
authors.initials: ML
authors.lastname: Paddock
authors.forename: Ron
authors.initials: R
authors.lastname: Mittler
authors.forename: Zvi Ioav
authors.initials: ZI
authors.lastname: Cabantchik
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.forename: Rachel
authors.initials: R
authors.lastname: Nechushtai
mesh_terms: D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000378:metabolism / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; C551999:NAF1 protein, human; D021122:Protein Subunits; D012261:Ribonucleoproteins; D054852:Small Molecule Libraries; D045162:Thiazolidinediones; D007501:Iron