Glutathione and the intracellular labile heme pool

AbstractOne candidate for the cytosolic labile iron pool is iron(II)glutathione. There is also a widely held opinion that an equivalent cytosolic labile heme pool exists and that this pool is important for the intracellular transfer of heme. Here we describe a study designed to characterise conjugates that form between heme and glutathione. In contrast to hydrated iron(II), heme reacts with glutathione, under aerobic conditions, to form the stable hematin–glutathione complex, which contains iron(III). Thus, glutathione is clearly not the cytosolic ligand for heme, indeed we demonstrate that the rate of heme degradation is enhanced in the presence of glutathione. We suggest that the concentration of heme in the cytosol is extremely low and that intracellular heme transfer occurs via intracellular membrane structures. Should any heme inadvertently escape into the cytosol, it would be rapidly conjugated to glutathione thereby protecting the cell from the toxic effects of heme.

Download Full-text

Faculty Opinions recommendation of Mitochondrial Hsp60, resistance to oxidative stress, and the labile iron pool are closely connected in Saccharomyces cerevisiae.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1009153.119858 ◽

2002 ◽

Author(s):

Thomas Nystrom

Keyword(s):

Oxidative Stress ◽

Saccharomyces Cerevisiae ◽

Labile Iron Pool ◽

Labile Iron ◽

Iron Pool

Download Full-text

Analysis of yggX and gshA Mutants Provides Insights into the Labile Iron Pool in Salmonella enterica

Journal of Bacteriology ◽

10.1128/jb.00639-08 ◽

2008 ◽

Vol 190 (23) ◽

pp. 7608-7613 ◽

Cited By ~ 11

Author(s):

Michael P. Thorgersen ◽

Diana M. Downs

Keyword(s):

Salmonella Enterica ◽

Iron Chelator ◽

Fenton Chemistry ◽

Labile Iron Pool ◽

Growth Defects ◽

Labile Iron ◽

Iron Pool ◽

Mutant Phenotypes ◽

Permeable Iron ◽

Iron Chelator Deferoxamine

ABSTRACT Strains of Salmonella enterica lacking YggX and the cellular reductant glutathione exhibit defects similar to those resulting from iron deficiency and oxidative stress. Mutant strains are sensitive to hydrogen peroxide and superoxide, deregulate the expression of the Fur-regulated gene entB, and fail to grow on succinate medium. Suppression of some yggX gshA mutant phenotypes by the cell-permeable iron chelator deferoxamine allowed the conclusion that increased levels of cellular Fenton chemistry played a role in the growth defects. The data presented are consistent with a scenario in which glutathione acts as a physiological chelator of the labile iron pool and in which YggX acts upstream of the labile iron pool by preventing superoxide toxicity.

Download Full-text

Phosphoinositide-3-kinase inhibition elevates ferritin level resulting depletion of labile iron pool and blocking of glioma cell proliferation

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2018.12.013 ◽

2019 ◽

Vol 1863 (3) ◽

pp. 547-564 ◽

Cited By ~ 2

Author(s):

Poonam Gupta ◽

Pratibha Singh ◽

Hriday S. Pandey ◽

Pankaj Seth ◽

Chinmay K. Mukhopadhyay

Keyword(s):

Cell Proliferation ◽

Glioma Cell ◽

Ferritin Level ◽

Kinase Inhibition ◽

Labile Iron Pool ◽

Glioma Cell Proliferation ◽

Labile Iron ◽

Phosphoinositide 3 Kinase ◽

Iron Pool

Download Full-text

Labile iron pool correlates with iron content in the nucleus and the formation of oxidative DNA damage in mouse lymphoma L5178Y cell lines.

Acta Biochimica Polonica ◽

10.18388/abp.2003_3729 ◽

2003 ◽

Vol 50 (1) ◽

pp. 211-215 ◽

Cited By ~ 15

Author(s):

Marcin Kruszewski ◽

Teresa Iwaneńko

Keyword(s):

Hydrogen Peroxide ◽

Dna Damage ◽

Cell Lines ◽

Oxidative Dna Damage ◽

Transition Metal Ions ◽

Dna Lesions ◽

Labile Iron Pool ◽

Labile Iron ◽

Iron Pool ◽

Mouse Lymphoma

Labile iron pool (LIP) constitutes a crossroad of metabolic pathways of iron-containing compounds and is midway between the cellular need for iron, its uptake and storage. In this study we investigated oxidative DNA damage in relation to the labile iron pool in a pair of mouse lymphoma L5178Y (LY) sublines (LY-R and LY-S) differing in sensitivity to hydrogen peroxide. The LY-R cells, which are hydrogen peroxide-sensitive, contain 3 times more labile iron than the hydrogen peroxide-resistant LY-S cells. Using the comet assay, we compared total DNA breakage in the studied cell lines treated with hydrogen peroxide (25 microM for 30 min at 4 degrees C). More DNA damage was found in LY-R cells than in LY-S cells. We also compared the levels of DNA lesions sensitive to specific DNA repair enzymes in both cell lines treated with H(2)O(2). The levels of endonuclease III-sensitive sites and Fapy-DNA glycosylase-sensitive sites were found to be higher in LY-R cells than in LY-S cells. Our data suggest that the sensitivity of LY-R cells to H(2)O(2) is partially caused by the higher yield of oxidative DNA damage, as compared to that in LY-S cells. The critical factor appears to be the availability of transition metal ions that take part in the OH radical-generating Fenton reaction (very likely in the form of LIP).

Download Full-text

The Cellular Labile Iron Pool and Intracellular Ferritin in K562 Cells

Blood ◽

10.1182/blood.v94.6.2128 ◽

1999 ◽

Vol 94 (6) ◽

pp. 2128-2134 ◽

Cited By ~ 109

Author(s):

Abraham M. Konijn ◽

Hava Glickstein ◽

Boris Vaisman ◽

Esther G. Meyron-Holtz ◽

Itzchak N. Slotki ◽

...

Keyword(s):

Biological Effects ◽

Ferritin Level ◽

Regulatory Protein ◽

Iron Chelation ◽

K562 Cells ◽

Iron Chelator ◽

Labile Iron Pool ◽

Cellular Iron ◽

Labile Iron ◽

Iron Pool

Abstract The labile iron pool (LIP) harbors the metabolically active and regulatory forms of cellular iron. We assessed the role of intracellular ferritin in the maintenance of intracellular LIP levels. Treating K562 cells with the permeant chelator isonicotinoyl salicylaldehyde hydrazone reduced the LIP from 0.8 to 0.2 μmol/L, as monitored by the metalo-sensing probe calcein. When cells were reincubated in serum-free and chelator-free medium, the LIP partially recovered in a complex pattern. The first component of the LIP to reappear was relatively small and occurred within 1 hour, whereas the second was larger and relatively slow to occur, paralleling the decline in intracellular ferritin level (t½= 8 hours). Protease inhibitors such as leupeptin suppressed both the changes in ferritin levels and cellular LIP recovery after chelation. The changes in the LIP were also inversely reflected in the activity of iron regulatory protein (IRP). The 2 ferritin subunits, H and L, behaved qualitatively similarly in response to long-term treatments with the iron chelator deferoxamine, although L-ferritin declined more rapidly, resulting in a 4-fold higher H/L-ferritin ratio. The decline in L-ferritin, but not H-ferritin, was partially attenuated by the lysosomotrophic agent, chloroquine; on the other hand, antiproteases inhibited the degradation of both subunits to the same extent. These findings indicate that, after acute LIP depletion with fast-acting chelators, iron can be mobilized into the LIP from intracellular sources. The underlying mechanisms can be kinetically analyzed into components associated with fast release from accessible cellular sources and slow release from cytosolic ferritin via proteolysis. Because these iron forms are known to be redox-active, our studies are important for understanding the biological effects of cellular iron chelation.

Download Full-text