Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster

Abstract

Maintenance of metal homeostasis is crucial for many different enzymatic activities and in turn for cell function and survival. In addition, cells display detoxification and protective mechanisms against toxic accumulation of metals. Perturbation of any of these processes normally leads to cellular dysfunction and finally to cell death. In the last years, loss of metal regulation has been described as a common pathological feature in many human neurodegenerative diseases. However, in most cases, it is still a matter of debate whether such dyshomeostasis is a primary or a secondary downstream defect. In this review, we will summarize and critically evaluate the contribution of Drosophila to model human diseases that involve altered metabolism of metals or in which metal dyshomeostasis influence their pathobiology. As a prerequisite to use Drosophila as a model, we will recapitulate and describe the main features of core genes involved in copper and zinc metabolism that are conserved between mammals and flies. Drosophila presents some unique strengths to be at the forefront of neurobiological studies. The number of genetic tools, the possibility to easily test genetic interactions in vivo and the feasibility to perform unbiased genetic and pharmacological screens are some of the most prominent advantages of the fruitfly. In this work, we will pay special attention to the most important results reported in fly models to unveil the role of copper and zinc in cellular degeneration and their influence in the development and progression of human neurodegenerative pathologies such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's Ataxia or Menkes, and Wilson's diseases. Finally, we show how these studies performed in the fly have allowed to give further insight into the influence of copper and zinc in the molecular and cellular causes and consequences underlying these diseases as well as the discovery of new therapeutic strategies, which had not yet been described in other model systems.

Characterizing the genetic basis of copper toxicity inDrosophilareveals a complex pattern of allelic, regulatory, and behavioral variation

“…In addition 538 to these copper-associated genes, we observed 64 genes with functions related to homeostasis 539 or detoxification of zinc, 2 genes involved with manganese regulation, and 19 genes involved in 540 binding unspecified metals. Of particular interest among these genes are Catsup (Q3), ZnT41F 541 (Q4), and stl (Q7), which are all associated with zinc transport or detoxification (Yepiskoposyan 542 et al 2006;Ozdowski et al 2009;Lye et al 2013;Navarro and Schneuwly 2017), trpl (Q5) and 543 DCP2 (Q8), which are hypothesized to be involved in manganese ion binding (Thurmond et al 544 2019), and swm (Q3), babo (Q5), and whd (Q5), which are thought to be involved in binding of 545 unspecified metal ions based on gene ontology prediction (Gaudet et al 2011;Thurmond et al 546 2019). 547…”

“…Although required for normal physiological function at low 29 concentrations, copper is one of many common environmental heavy metal pollutants linked to 30 mining (Ramirez et al 2005;Wuana and Okieimen 2011;Wright et al 2015), pipes used to 31 provide drinking water (Harvey et al 2016), and pesticide use (de Oliveira-Filho et al 2004). In its 32 essential role, copper helps bind oxygen, catalyzes enzymatic reactions, and promotes normal 33 neurological development (Hart et al 1928;Danks 1988;World Health Organization et al 1996;34 Uriu-Adams and Keen 2005; Norgate et al 2006;Navarro and Schneuwly 2017). However, 35 excessive copper exposure ultimately leads to the accumulation of reactive oxygen species, 36 which can cause cellular damage through oxidative stress (Uriu-Adams and Keen 2005;37 Tchounwou et al 2008).…”

“…MTF-1 binds to metal 42 responsive elements of MT genes, increasing MT abundance in copper accumulating cells and 43 allowing excess heavy metal ions to be sequestered until they are removed from the system 44 (Filshie et al 1971;Stuart et al 1985;Mokdad et al 1987;Egli et al 2003;Balamurugan et al 45 2004; Southon et al 2004). Metal chaperone and transporter proteins such as Ccs (Culotta et al 46 1997), Atox1 (Southon et al 2004;Hatori and Lutsenko 2013), ATP7 (Norgate et al 2006), and 47 CTR1 family transporters (Petris et al 2003;Guo et al 2004;Balamurugan et al 2007;Turski and 48 Thiele 2007;Calap-Quintana et al 2017;Navarro and Schneuwly 2017) play a crucial role in the 49 response to heavy metal toxicity as well (Egli et al 2003;Petris et al 2003;Yepiskoposyan et al 50 2006;Janssens et al 2009). For example, in Drosophila melanogaster, high copper exposure 51 decreases translation of Ctr1A and Ctr1B via MTF-1 to reduce influx of copper ions (Balamurugan 52 et al 2007;Turski and Thiele 2007;Calap-Quintana et al 2017;Navarro and Schneuwly 2017), 53…”

The Evolution of Insect Metallothioneins

“…Over time, these detoxification strategies have also been used to detoxify other non-essential heavy metals such as cadmium (Cd) (Klaassen et al 1999). The detoxification strategies are diverse and can often be taxon-specific (Cobbett and Goldsbrough 2002;Navarro and Schneuwly 2017). One common mechanism among many organisms is the use of low molecular weight, cysteine-rich peptides known as metallothioneins (MTs) to chelate and regulate the concentration of heavy metals in the cell (Hamer 1986).…”

Biocontrol of phytobacteria with bacteriophage cocktails

“…The continuous use of copper results in its accumulation in the environment, which has been linked to human health problems, toxic effects on flora and fauna, and the development of copper‐tolerant phytopathogens . Human and animal health concerns that have been associated with copper toxicity include gastrointestinal, hepatic, reproductive and neurodegenerative disorders such as Alzheimer's disease . Indian childhood cirrhosis is a disorder that has been linked to the intake of large quantities of copper in genetically susceptible individuals .…”