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.