The indispensable role of mammalian iron sulfur proteins in function and regulation of multiple diverse metabolic pathways

Abstract

In recent years, iron sulfur (Fe–S) proteins have been identified as key players in mammalian metabolism, ranging from long-known roles in the respiratory complexes and the citric acid cycle, to more recently recognized roles in RNA and DNA metabolism. Fe–S cofactors have often been missed because of their intrinsic lability and oxygen sensitivity. More Fe–S proteins have now been identified owing to detection of their direct interactions with components of the Fe–S biogenesis machinery, and through use of informatics to detect a motif that binds the co-chaperone responsible for transferring nascent Fe–S clusters to domains of recipient proteins. Dissection of the molecular steps involved in Fe–S transfer to Fe–S proteins has revealed that direct and shielded transfer occurs through highly conserved pathways that operate in parallel in the mitochondrial matrix and in the cytosolic/nuclear compartments of eukaryotic cells. Because Fe–S clusters have the unusual ability to accept or donate single electrons in chemical reactions, their presence renders complex chemical reactions possible. In addition, Fe–S clusters may function as sensors that interconnect activity of metabolic pathways with cellular redox status. Presence in pathways that control growth and division may enable cells to regulate their growth according to sufficiency of energy stores represented by redox capacity, and oxidation of such proteins could diminish anabolic activities to give cells an opportunity to restore energy supplies. This review will discuss mechanisms of Fe–S biogenesis and delivery, and methods that will likely reveal important roles of Fe–S proteins in proteins not yet recognized as Fe–S proteins.

Paramagnetic NMR Spectroscopy Is a Tool to Address Reactivity, Structure, and Protein–Protein Interactions of Metalloproteins: The Case of Iron–Sulfur Proteins

“…Iron-sulfur (Fe-S) proteins play crucial roles in mammalian metabolism [166]. The study of the components of the Fe-S biogenesis machineries has led to the identification of a large number of proteins, whose importance for life is documented by an increasing number of diseases linked to these components and their biogenesis.…”

Chronic Pressure Overload Results in Deficiency of Mitochondrial Membrane Transporter ABCB7 Which Contributes to Iron Overload, Mitochondrial Dysfunction, Metabolic Shift and Worsens Cardiac Function

“…ABCB6 regulates porphyrin transport 15 . Our current knowledge on ABCB7 function remains presumptive 11–14,16–26 . ABCB7 function in the heart is also not known.…”

“…In recent times, there is a growing interest in the link among mitochondrial ABC transporters, iron metabolism, and cardiovascular diseases 2–4,16–29 . The heart is a highly metabolically active organ which requires a continuous supply of ATP to sustain its contractile function.…”

Mitochondrial diseases: expanding the diagnosis in the era of genetic testing

“…To date, there are at least 18 known Fe/S cluster assembly proteins involved in proper biogenesis and trafficking of Fe/S containing clusters within mitochondria. A full review of this process is beyond the scope of this article but can be found elsewhere [229][230][231] .…”