Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism.

Zvonimir Marelja,Fanis Missirlis,Silke Leimkühler

doi:10.3389/fphys.2018.00050

Abstract

Iron sulfur (Fe-S) clusters and the molybdenum cofactor (Moco) are present at enzyme sites, where the active metal facilitates electron transfer. Such enzyme systems are soluble in the mitochondrial matrix, cytosol and nucleus, or embedded in the inner mitochondrial membrane, but virtually absent from the cell secretory pathway. They are of ancient evolutionary origin supporting respiration, DNA replication, transcription, translation, the biosynthesis of steroids, heme, catabolism of purines, hydroxylation of xenobiotics, and cellular sulfur metabolism. Here, Fe-S cluster and Moco biosynthesis in Drosophila melanogaster is reviewed and the multiple biochemical and physiological functions of known Fe-S and Moco enzymes are described. We show that RNA interference of Mocs3 disrupts Moco biosynthesis and the circadian clock. Fe-S-dependent mitochondrial respiration is discussed in the context of germ line and somatic development, stem cell differentiation and aging. The subcellular compartmentalization of the Fe-S and Moco assembly machinery components and their connections to iron sensing mechanisms and intermediary metabolism are emphasized. A biochemically active Fe-S core complex of heterologously expressed fly Nfs1, Isd11, IscU, and human frataxin is presented. Based on the recent demonstration that copper displaces the Fe-S cluster of yeast and human ferredoxin, an explanation for why high dietary copper leads to cytoplasmic iron deficiency in flies is proposed. Another proposal that exosomes contribute to the transport of xanthine dehydrogenase from peripheral tissues to the eye pigment cells is put forward, where the Vps16a subunit of the HOPS complex may have a specialized role in concentrating this enzyme within pigment granules. Finally, we formulate a hypothesis that (i) mitochondrial superoxide mobilizes iron from the Fe-S clusters in aconitase and succinate dehydrogenase; (ii) increased iron transiently displaces manganese on superoxide dismutase, which may function as a mitochondrial iron sensor since it is inactivated by iron; (iii) with the Krebs cycle thus disrupted, citrate is exported to the cytosol for fatty acid synthesis, while succinyl-CoA and the iron are used for heme biosynthesis; (iv) as iron is used for heme biosynthesis its concentration in the matrix drops allowing for manganese to reactivate superoxide dismutase and Fe-S cluster biosynthesis to reestablish the Krebs cycle.

Highlights

We describe the biosynthesis of molybdenum cofactor (Moco) (Rajagopalan, 1997; Mendel and Leimkühler, 2015; Leimkühler, 2017), whose basic structure has two sulfur atoms of the tricyclic pyranopterin molecule molybdopterin (MPT) coordinating the Mo atom (Rajagopalan et al, 1982)
Turning to Moco biosynthesis, an ancient, ubiquitous and highly conserved pathway underpinning molybdenum biochemistry (Rajagopalan, 1997; Mendel and Leimkühler, 2015; Leimkühler, 2017), it can be divided into three major steps: (i) guanosine triphosphate (GTP) is converted to cyclic pyranopterin monophosphate (cPMP), (ii) cPMP is converted to MPT by generation of the dithiolene group, and (iii) molybdate is ligated to MPT forming Moco (Figure 1)
RNA interference (RNAi) of Nfs1 in the circadian clock neurons resulted in loss of rhythmic activity of flies monitored under constant darkness (Mandilaras and Missirlis, 2012)

Summary

INTRODUCTION

In the first known biochemical reactions on earth, molybdenum and iron-sulfur (Fe-S) clusters enabled electron transfers turning inorganic molecules into hydrogenated carbon molecules (Mortenson, 1964; Eck and Dayhoff, 1966; Hall et al, 1971; Ochiai, 1978; Wächtershäuser, 1988; Russell and Martin, 2004; Zhang and Gladyshev, 2008; Nitschke and Russell, 2009; Schoepp-Cothenet et al, 2012; Stüeken et al, 2015). Reducing FeS cluster biosynthesis in Drosophila with either RNA interference (RNAi) of frataxin or loss-of-function Hsc mutants lead to mitochondrial iron accumulation and reduced ferritin expression (Anderson et al, 2005; Uhrigshardt et al, 2013; Navarro et al, 2015), offering a testable potential explanation of why excess dietary copper affects ferritin iron accumulation In this respect, we note that copper chelation ameliorated a fly model of Friedreich’s ataxia (Soriano et al, 2016) and that the dithiol Drosophila glutaredoxin-1 was implicated in copper homeostasis (Mercer and Burke, 2016)

A Mitochondrial Iron Sulfur Enzyme

Findings

CONCLUSION