Cardiac Copper Deficiency Activates a Systemic Signaling Mechanism that Communicates with the Copper Acquisition and Storage Organs

Kim, Byung-Eun; Turski, Michelle L.; Nose, Yohei; Casad, Michelle; Rockman, Howard A.; Thiele, Dennis J.

doi:10.1016/j.cmet.2010.04.003

Cited by 151 publications

(152 citation statements)

References 63 publications

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“…4A), and enterocyte Atp7a expression was increased significantly (Fig. 4B), consistent with previous observations made in CuD mice (12). More importantly, cyto-FOX activity was not different in the normal controls compared with the anemic CuD rats (Fig.…”

Section: Fox Activity In Cytosolic Fractions Prepared By Additional Msupporting

confidence: 80%

Discovery of a cytosolic/soluble ferroxidase in rodent enterocytes

Ranganathan

Fuqua

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hephaestin (Heph), a membrane-bound multicopper ferroxidase (FOX) expressed in duodenal enterocytes, is required for optimal iron absorption. However, sex-linked anemia (sla) mice harboring a 194-amino acid deletion in the Heph protein are able to absorb dietary iron despite reduced expression and mislocalization of the mutant protein. Thus Heph may not be essential, and mice are able to compensate for the loss of its activity. The current studies were undertaken to search for undiscovered FOXs in rodent enterocytes. An experimental approach was developed to investigate intestinal FOXs in which separate membrane and cytosolic fractions were prepared and FOX activity was measured by a spectrophotometric transferrin-coupled assay. Unexpectedly, FOX activity was noted in membrane and cytosolic fractions of rat enterocytes. Different experimental approaches demonstrated that cytosolic FOX activity was not caused by contamination with membrane Heph or a method-induced artifact. Cytosolic FOX activity was abolished by SDS and heat (78°C), suggesting protein-mediated iron oxidation, and was also sensitive to Triton X-100. Furthermore, cytosolic FOX activity increased ∼30% in iron-deficient rats (compared with controls) but was unchanged in copper-deficient rats (in contrast to the reported dramatic reduction of Heph expression and activity during copper deficiency). Additional studies done in sla, Heph-knockout, and ceruloplasmin-knockout mice proved that cytosolic FOX activity could not be fully explained by Heph or ceruloplasmin. Therefore rodent enterocytes contain a previously undescribed soluble cytosolic FOX that may function in transepithelial iron transport and complement membranebound Heph.intestine | ferrozine | cyto-FOX

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Section: Fox Activity In Cytosolic Fractions Prepared By Additional Msupporting

confidence: 80%

Discovery of a cytosolic/soluble ferroxidase in rodent enterocytes

Ranganathan

Fuqua

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, a similar pattern of heightened serum Cu and reduced kidney and spleen Cu was seen in infections with Coxsackie virus (57), indicating that such fluxes in whole-animal Cu may be common to diverse infectious agents. Elegant studies by Kim et al (58) have demonstrated a cross-tissue communication of Cu status whereby Cu deficiencies in one tissue (e.g., heart) send out a signal to mobilize Cu from other tissues (e.g., liver) to compensate for the metal deficiency (58,59). It is possible that a similar communication occurs during infection to account for the fluxes in tissue and blood stream Cu we report here.…”

Section: Resultsmentioning

confidence: 73%

Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase

Gleason

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

104

150

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Copper is both an essential nutrient and potentially toxic metal, and during infection the host can exploit Cu in the control of pathogen growth. Here we describe a clever adaptation to Cu taken by the human fungal pathogen Candida albicans. In laboratory cultures with abundant Cu, C. albicans expresses a Cu-requiring form of superoxide dismutase (Sod1) in the cytosol; but when Cu levels decline, cells switch to an alternative Mn-requiring Sod3. This toggling between Cu- and Mn-SODs is controlled by the Cu-sensing regulator Mac1 and ensures that C. albicans maintains constant SOD activity for cytosolic antioxidant protection despite fluctuating Cu. This response to Cu is initiated during C. albicans invasion of the host where the yeast is exposed to wide variations in Cu. In a murine model of disseminated candidiasis, serum Cu was seen to progressively rise over the course of infection, but this heightened Cu response was not mirrored in host tissue. The kidney that serves as the major site of fungal infection showed an initial rise in Cu, followed by a decline in the metal. C. albicans adjusted its cytosolic SODs accordingly and expressed Cu-Sod1 at early stages of infection, followed by induction of Mn-Sod3 and increases in expression of CTR1 for Cu uptake. Together, these studies demonstrate that fungal infection triggers marked fluctuations in host Cu and C. albicans readily adapts by modulating Cu uptake and by exchanging metal cofactors for antioxidant SODs.

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“…In C. elegans, several neuropeptides are known to mediate intestinal function to regulate metabolism and development (55)(56)(57), although a hepcidin homolog has not been found. Cardiac copper deficiency caused by depletion of the Ctr1 copper importer in the heart induced a significant up-regulation of ATP7A in the intestine of mice, which may lead to increased copper supply into circulation (58). This study suggested that cross-talk may take place between tissue types to coordinate systemic copper homeostasis.…”

Section: Discussionmentioning

confidence: 90%