Fe-S Proteins Acting as Redox Switch: New Key Actors of Cellular Adaptive Responses

Abstract

Iron-sulfur (Fe-S) clusters are inorganic prosthetic groups composed of only iron and inorganic sulfur atoms with variable nuclearities. Found in all kingdoms of life, they perform numerous critical functions in fundamental processes (e.g. respiration, photosynthesis, nitrogen fixation). Organisms develop different pathways to sense their local environment such as nutrient availability, level of oxidative stress or of an element such as iron, and to respond and adapt to changes. The chemistry of Fe-S clusters makes them ideal for sensing various redox environmental signals and subsequently for mediating appropriate cellular responses. Fe-S cluster-containing sensors can lose their cluster, accommodate another type of cluster (e.g. interconversion between [4Fe-4S] and [2Fe-2S] clusters) or receive/give electrons (change in the redox state of the cluster). The present review focuses on the latter sensing mechanism, which controls the activity of Fe-S proteins in response to redox signals by change in the redox state of its cluster. Proteins using this mechanism can be found in bacteria, yeasts as well as mammals and are involved in enzyme protection (FeSII), Fe-S cluster transfer/repair (mitoNEET), DNA repair (Base Excision Repair (BER) glycosylases and helicases), and regulation of gene expression (ThnY, AirS, SoxR). In all these proteins, when the Fe-S cluster is reduced, proteins are in a "dormant state". When their cluster perceives a signal that induces its oxidation, they switch to an "active state". This sensing mechanism efficiently helps cells to turn on survival pathways quickly and recover from stressful conditions.

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

“…Moreover, this study confirms the critical role of CISD2 at the crossroads between the apoptosis and autophagy regulation pathways [ 63 ]. We know that its Fe-S cluster is redox active and that at least some of its biochemical properties are regulated by the redox state of its cluster [ 64 ]. More biochemical studies are needed to describe finely how CISD2 can regulate the autophagy/apoptosis pathways and the exact role of its cluster in this regulation.…”

The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease

“…These proteins are well characterized as electron transfer proteins [ 5 ]. However, in recent years, evidence for additional functions such as sensors of iron or oxygen [ 6 , 7 ], enzymes [ 4 ], and gene expression regulation [ 8 ] were attributed to Fe-S proteins. In addition, in recent years, an increased number of human diseases were found to be associated with dysfunctions of the Fe-S cluster biogenesis pathway [ 8 – 11 ].…”

“…The fingerprint absorption peak of the NEET proteins’ cluster in its oxidized form was found to be 458 nm; upon reduction this peak absorption is highly decreased [ 26 , 39 ]. The ~ 90% decrease in the 458 nm absorption, under reducing conditions, can be fully recovered by exposing the NEET proteins to oxygen, proving that the [2Fe-2S] cluster of the NEET proteins is redox-active [ 7 , 20 , 26 ]. For a detailed description of the biophysical properties of the NEET cluster please refer to our previous review published by Tamir and his coworkers in BBA review— Biochimica et Biophysica Acta (BBA) - Molecular Cell Research [ 39 ].…”

Fe‐S Clusters Emerging as Targets of Therapeutic Drugs

“…Fe-S cluster destabilization or/and alteration often lead to the apo form of the protein. As a consequence, the protein can switch to another function (case of the aconitase), be “repaired” as a new Fe-S center might be loaded, or be ultimately degraded (see [ 4 ] for review). β -Phenethyl isothiocyanate (PEITC) is a natural product with potent anticancer activity against human leukemia.…”

“…Due to their exceptional plasticity, Fe-S clusters can sense mild redox changes and act as cellular redox switches, thanks to redox or nuclearity changes, or even to degradation [ 4 ]. As so, biological functions associated to Fe-S-containing proteins can be modulated through oxidation, and these regulations have been particularly well studied in bacteria.…”