Wu G et al. (2023) MicroPubl Biol "SGK-1 mediated inhibition of iron import is a determinant of lifespan in C. elegans."

Wu G, Baumeister R, Heimbucher T

[MicroPubl Biol, 2023]

Maintaining iron levels is crucial for health, but iron overload has been associated with tumorigenesis. Therefore, critical enzymes involved in iron homeostasis are under tight, typically posttranslational control. In <i>C. elegans</i> , the mTORC2 and insulin/IGF-1 activated kinase SGK-1 is induced upon exogenous iron overload to couple iron storage and fat accumulation. Here we show that, already at physiological iron conditions, <i>sgk-1</i> loss-of-function increases intracellular iron levels that may impair lifespan. Reducing iron levels by diminishing cellular or mitochondrial iron import is sufficient to extend the short lifespan of <i>sgk-1</i> loss-of-function animals. Our results indicate another regulatory level of <i>sgk-1</i> in iron homeostasis via negative feedback regulation on iron transporters.

Tong WH et al. (2006) Cell Metab "Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis."

Tong WH, Rouault TA

[Cell Metab, 2006]

Iron-sulfur (Fe-S) clusters are required for the functions of mitochondrial aconitase, mammalian iron regulatory protein 1, and many other proteins in multiple subcellular compartments. Recent studies in Saccharomyces cerevisiae indicated that Fe-S cluster biogenesis also has an important role in mitochondrial iron homeostasis. Here we report the functional analysis of the mitochondrial and cytosolic isoforms of the human Fe-S cluster scaffold protein, ISCU. Suppression of human ISCU by RNAi not only inactivated mitochondrial and cytosolic aconitases in a compartment-specific manner but also inappropriately activated the iron regulatory proteins and disrupted intracellular iron homeostasis. Furthermore, endogenous ISCU levels were suppressed by iron deprivation. These results provide evidence for a coordinated response to iron deficiency that includes activation of iron uptake, redistribution of intracellular iron, and decreased utilization of iron in Fe-S proteins.

Kortman GA et al. (2015) Eur J Immunol "Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens."

Kortman GA, Cherayil BJ, Swinkels DW, Tjalsma H, Wiegerinck ET, Bolhuis A, Richters TJ, Timmerman HM, Boekhorst J, Shanmugam NK, Mulder ML, Roelofs R, Trebicka E, Laarakkers CM

[Eur J Immunol, 2015]

Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition.

Xu J et al. (2010) Mech Ageing Dev "The emerging role of iron dyshomeostasis in the mitochondrial decay of aging."

Leeuwenburgh C, Marzetti E, Prolla TA, Kim JS, Xu J, Seo AY

[Mech Ageing Dev, 2010]

Recent studies show that cellular and mitochondrial iron increases with age. Iron overload, especially in mitochondria, increases the availability of redox-active iron, which may be a causal factor in the extensive age-related biomolecular oxidative damage observed in aged organisms. Such damage is thought to play a major role in the pathogenesis of iron overload diseases and age-related pathologies. Indeed, recent findings of the beneficial effects of iron manipulation in life extension in Caenorhabditis elegans, Drosophila and transgenic mice have sparked a renewed interest in the potential role of iron in longevity. A substantial research effort now focuses on developing and testing safe pharmacologic interventions to combat iron dyshomeostasis in aging, acute injuries and in iron overload disorders.

McColl, Gawain et al. (2013) International Worm Meeting "Does iron dyshomeostasis drive ageing?"

McColl, Gawain, James, S.A., Cherny, R.A., Bush, A.I., Roberts, B.R.

[International Worm Meeting, 2013]

Iron has been implicated in the ageing process as a causative factor in the free radical theory of ageing through mechanisms of oxidative chemistry. To explore iron homeostasis in an ageing model, we employed novel analytical approaches to characterize age-related iron changes in Caenorhabditis elegans. Using live animals we imaged iron during ageing via x-ray fluorescence microscopy. We observed dramatic intestinal-iron accumulation with age, which correlated with increased reactive oxygen species. Insulin-like signaling modulates these effects, so that long-lived daf-2 mutants are resistant to these age-related changes, while short-lived daf-16 mutants show more marked effects. To identify the iron-protein complexes that are changing with age, we developed a native liquid chromatography and mass spectrometry technique. We observed that wild-type life span requires the ability to store iron in ferritin, however, iron storage is not required for long-lived phenotype of daf-2 mutants. When challenged with exogenous iron, wild-types can safely store this iron with minimal effects on longevity. When daf-2 mutants are exposed to equivalently elevated iron we observed a significant reduction in lifespan, indicating daf-2 mutant longevity is associated with altered iron homeostasis. These data indicate a causal role of iron homeostasis in longevity.

Zhang J et al. (2019) Cell Host Microbe "A Delicate Balance between Bacterial Iron and Reactive Oxygen Species Supports Optimal C.elegans Development."

Zhang J, Holdorf AD, Walhout AJM, Shang Y, Yilmaz LS, Artal-Sanz M, Olmedo M, Li X

[Cell Host Microbe, 2019]

Iron is an essential micronutrient for all forms of life; low levels of iron cause human disease, while too much iron is toxic. Low iron levels induce reactive oxygenspecies (ROS) by disruption of the heme and iron-sulfur cluster-dependent electron transport chain (ETC). To identify bacterial metabolites that affect development, we screened the Keio Escherichia coli collection and uncovered 244 gene deletion mutants that slow Caenorhabditis elegans development. Several of these genes encode members of the ETC cytochrome bo oxidase complex, as well as iron importers.Surprisingly, either iron or anti-oxidant supplementation reversed the developmental delay. This suggests that low bacterial iron results in high bacterial ROS and vice versa, which causes oxidative stress in C.elegans that subsequently impairs mitochondrial function and delays development. Our data indicate that the bacterial diets of C.elegans provide precisely tailored amounts of iron to support proper development.

Anderson CP et al. (2014) Front Pharmacol "Mechanisms of iron metabolism in Caenorhabditis elegans."

Anderson CP, Leibold EA

[Front Pharmacol, 2014]

Iron is involved in many biological processes essential for sustaining life. In excess, iron is toxic due to its ability to catalyze the formation of free radicals that damage macromolecules. Organisms have developed specialized mechanisms to tightly regulate iron uptake, storage and efflux. Over the past decades, vertebrate model organisms have led to the identification of key genes and pathways that regulate systemic and cellular iron metabolism. This review provides an overview of iron metabolism in the roundworm Caenorhabditis elegans and highlights recent studies on the role of hypoxia and insulin signaling in the regulation of iron metabolism. Given that iron, hypoxia and insulin signaling pathways are evolutionarily conserved, C. elegans provides a genetic model organism that promises to provide new insights into mechanisms regulating mammalian iron metabolism.

Kim YI et al. (2004) J Mol Biol "Transcriptional regulation and life-span modulation of cytosolic aconitase and ferritin genes in C.elegans."

Kim YI, Cho JH, Yoo OJ, Ahnn J

[J Mol Biol, 2004]

Ferritin is the major iron storage protein regulating cytosolic concentration of iron by storing excess iron. Vertebrate ferritins are heteropolymeric proteins composed of heavy chain and light chain subunits. We have characterized two Caenorhabditis elegans genes (ftn-1 and ftn-2), which encode ferritin homologs showing high degree of similarity to mammalian ferritin heavy chains. Even though these two ferritins are more than 78% identical in amino acid sequence, our data show that expression patterns and responses to iron are quite different. Cytosolic aconitase (aco-1), iron regulatory protein, is known to regulate cellular iron concentration by modulating translation of the ferritin mRNA in addition to its enzymatic activity that converts citrate into iso-citrate. We have shown that the expression levels of aco-1 and ftn-1 genes are both regulated by iron treatment but in opposite ways. Interestingly, mutant animals lacking ACO-1 and FTN-1 show significantly reduced life-span upon iron stress, while N2 and ftn-2 animals show no difference. Our results suggest that ftn-1 and aco-1 are transcriptionally regulated by iron and are important for iron homeostasis affecting life-span upon iron stress conditions in C.elegans.

Young-Il Kim et al. (2004) East Asia Worm Meeting "Life-span modulation and Transcriptional regulation of cytosolic aconitase and ferritin genes in C. elegans"

Jeong Hoon Cho, Ook Joon Yoo, Young-Il Kim, Joohong Ahnn

[East Asia Worm Meeting, 2004]

Ferritin is the major iron storage protein regulating cytosolic concentration of iron by storing excess iron. Vertebrate ferritins are heteropolymeric proteins composed of heavy chain and light chain subunits. Two ferritin homologues of C. elegans showing high similarity with mammalian ferritin heavy chains have been characterized. Even though these two ferritins are almost identical in amino acid sequence, our data show that expression patterns and responses to iron of these two genes ( ftn-1 and ftn-2 ) are quite different. Another iron regulatory protein, cytosolic aconitase ( aco-1 ) is known to regulate cellular iron concentration by modulating translation of the ferritin mRNA in addition to its enzymatic activity that converts citrate into iso-citrate. In C. elegans , the expression levels of aco-1 and ferritin genes are both regulated by iron treatment but in opposite ways. Interestingly, aco-1(jh131) and ftn-1(RNAi) animals show significantly reduced life-span upon iron stress, while N2 and ftn-2(ok404) animals show no difference. Our results suggest that ftn-1 and aco-1 are transcriptionally regulated inversely by iron and are important for iron homeostasis affecting life-span in C. elegans .

Dawes AT et al. (2013) J Theor Biol "Cortical geometry may influence placement of interface between Par protein domains in early Caenorhabditis elegans embryos."

Iron D, Dawes AT

[J Theor Biol, 2013]

During polarization, proteins and other polarity determinants segregate to the opposite ends of the cell (the poles) creating biochemically and dynamically distinct regions. Embryos of the nematode worm Caenorhabditis elegans (C. elegans) polarize shortly after fertilization, creating distinct regions of Par protein family members. These regions are maintained through to first cleavage when the embryo divides along the plane specified by the interface between regions, creating daughter cells with different protein content. In wild type single cell embryos the interface between these Par protein regions is reliably positioned at approximately 60% egg length, however, it is not known what mechanisms are responsible for specifying the position of the interface. In this investigation, we use two mathematical models to investigate the movement and positioning of the interface: a biologically based reaction-diffusion model of Par protein dynamics, and the analytically tractable perturbed Allen-Cahn equation. When we numerically simulate the models on a static 2D domain with constant thickness, both models exhibit a persistently moving interface that specifies the boundary between distinct regions. When we modify the simulation domain geometry, movement halts and the interface is stably positioned where the domain thickness increases. Using asymptotic analysis with the perturbed Allen-Cahn equation, we show that interface movement depends explicitly on domain geometry. Using a combination of analytic and numeric techniques, we demonstrate that domain geometry, a historically overlooked aspect of cellular simulations, may play a significant role in spatial protein patterning during polarization.