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

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.

Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster

“…Similarly, high levels of dietary copper have long been known to reduce midgut iron accumulation ( Poulson and Bowen 1952 ) and whole-body iron stores ( Bettedi et al 2011 ). The mechanism involved remains to be established but might involve inhibition of iron-sulfur cluster biosynthesis by copper ( Vallières et al 2017 ; Marelja et al 2018 ). Finally, behavioral adaptations ( e.g.…”

Inhibition of mitochondrial respiration under hypoxia and increased antioxidant activity after reoxygenation of Tribolium castaneum

“…The enzyme citrate synthase exists in the mitochondrial matrix and functions in the first step of the citric acid cycle of all living organisms. It is usually used as a quantitative enzyme marker for the presence of mitochondria, aerobic capacity, and mitochondria density in cells [ 57 – 60 ]. The decreased citrate synthase under hypoxia suggests that low oxygen might suppress mitochondrial activity.…”

Copper in the suprachiasmatic circadian clock: A possible link between multiple circadian oscillators

“…The relationship between trace metals, circadian rhythms, and metabolism is still largely uninvestigated, but several studies in plants demonstrate rhythms in copper and iron homeostasis and how they pertain to circadian activity and metabolism (Andres‐Colas et al., ; Penarrubia et al., ; Perea‐Garcia, Sanz, et al., ; Tissot et al., ). As Cu plays a role in iron homeostasis, it is noteworthy that a circadian rhythm in iron levels in the midbrain of mice has been reported (Unger et al., , ), and there is growing evidence of evolutionarily conserved, circadian control of iron homeostasis and vice‐versa (Ben‐Shlomo et al., ; Botebol et al., ; Cao, Li, Jin, & Hu, ; Dean, Allen, O'Donnell, & Earley, ; Mandilaras & Missirlis, ; Marelja, Leimkuhler, & Missirlis, ; Okazaki et al., ; Robles et al., ; Saha et al., ; Simcox et al., ; Tissot et al., ; Zhang et al., ). In addition, iron deficiency has been shown to affect circadian wheel‐running activity and is strongly associated with restless leg syndrome, which has a circadian component and manifests as a sleep disorder (Dowling et al., ; Earley et al., ; Furudate, Komada, Kobayashi, Nakajima, & Inoue, ).…”