Accumulation of heme in mitochondria from rabbit reticulocytes with inhibited globin synthesis

Ponka, P; Borová, J; Neuwirt, J

doi:10.1016/0304-4165(73)90217-1

Cited by 32 publications

(17 citation statements)

References 9 publications

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“…Deficiency for complex IV, which is the case in AD (5,7), is likely to increase the production of free radicals in the mitochondrial matrix (33). Up-regulation of heme-b biosynthesis in the mitochondrial matrix could lead to elevated heme-b in this compartment (13). High levels of heme-b, whatever the possible metabolic advantage, are associated with a risk of oxidative damage, as heme is a prooxidant (34).…”

Section: Discussionmentioning

confidence: 99%

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A role for heme in Alzheimer's disease: Heme binds amyloid β and has altered metabolism

Atamna

Frey

2004

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

235

239

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Heme is a common factor linking several metabolic perturbations in Alzheimer's disease (AD), including iron metabolism, mitochondrial complex IV, heme oxygenase, and bilirubin. Therefore, we determined whether heme metabolism was altered in temporal lobes obtained at autopsy from AD patients and age-matched nondemented subjects. AD brain demonstrated 2.5-fold more heme-b (P < 0.01) and 26% less heme-a (P ‫؍‬ 0.16) compared with controls, resulting in a highly significant 2.9-fold decrease in heme-a͞heme-b ratio (P < 0.001). Moreover, the strong Pearson correlation between heme-a and heme-b measured in control individuals (r 2 ‫؍‬ 0.66, P < 0.002, n ‫؍‬ 11) was abolished in AD subjects (r 2 ‫؍‬ 0.076, P ‫؍‬ 0.39, n ‫؍‬ 12). The level of ferrochelatase (which makes heme-b in the mitochondrial matrix) in AD subjects was 4.2 times (P < 0.04) that in nondemented controls, suggesting up-regulated heme synthesis. To look for a possible connection between these observations and established mechanisms in AD pathology, we examined possible interactions between amyloid ␤ (A␤) and heme. A␤(1-40) and A␤(1-42) induced a redshift of 15-20 nm in the spectrum of heme-b and heme-a, suggesting that heme binds A␤, likely to one or more of the histidine residues. Lastly, in a tissue culture model, we found that clioquinol, a metal chelator in clinical trials for AD therapy, decreased intracellular heme. In light of these observations, we have proposed a model of AD pathobiology in which intracellular A␤ complexes with free heme, thereby decreasing its bioavailability (e.g., heme-a) and resulting in functional heme deficiency. The model integrates disparate observations, including A␤, mitochondrial dysfunction, cholesterol, and the proposed efficacy of clioquinol.mitochondria ͉ heme-a ͉ iron ͉ clioquinol ͉ ferrochelatase H eme (ferriprotoporphyrin IX) metabolism appears altered in the brains of Alzheimer's disease (AD) patients. Heme oxygenase (HO) increases in AD (1, 2), and the level of bilirubin (one of the products of heme degradation by HO) is increased in AD patients (3). Mitochondrial complex IV, the only enzyme in cells that contains heme-a (see below) (4), declines in AD (5-8). Heme-a is rate limiting for the assembly of complex IV (9). Furthermore, an inhibitor of muscarinic acetylcholine receptor binding, which increased in AD brain, was suggested to be heme (10, 11). Therefore, we studied heme metabolism in AD brain and nondemented age-matched normal subjects.Heme-b, the product of ferrochelatase (FC) (also known as protoheme), is produced in the mitochondrial matrix (12, 13) and is the precursor for heme-c and heme-a. The structure of heme-c is similar to that of heme-b, but it is covalently attached to a few specific proteins (reviewed in ref. 14). Heme-b and heme-a exist in two major pools in the cell, free and protein-associated. Conversion of heme-b to heme-a requires farnasylation and oxidation (15). Farnesyl-pyrophsphate (FPP) is the precursor for the farnesyl moiety in heme-a, cholesterol, dolichol, farnesylation ...

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Section: Discussionmentioning

confidence: 99%

“…Heme-b, the product of ferrochelatase (FC) (also known as protoheme), is produced in the mitochondrial matrix (12,13) and is the precursor for heme-c and heme-a. The structure of heme-c is similar to that of heme-b, but it is covalently attached to a few specific proteins (reviewed in ref.…”

mentioning

confidence: 99%

A role for heme in Alzheimer's disease: Heme binds amyloid β and has altered metabolism

Atamna

Frey

2004

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

235

239

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“…Once formed, heme must be translocated from mitochondria to sites of hemoprotein syntheses in the cytoplasm and endoplasmic reticulum. Endogenously synthesized heme does not freely penetrate the inner membrane of the mitochondria, consequently, the transport of heme across this membrane seems to be a potential rate-limiting step in hemoprotein syntheses (52,53). The efflux of heme from mitochondria depends on the presence of cytosolic protein (54).…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of a Newly Identified Heme-binding Protein Induced during Differentiation of urine Erythroleukemia Cells

Taketani

Adachi

Kohno³

et al. 1998

Journal of Biological Chemistry

111

110

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“…␦-Aminolevulinic acid synthase (ALAS) catalyzes the condensation of succinyl-CoA with glycine, producing ALA (13), which is the first and rate-limiting step in heme synthesis. Ferrochelatase, located in the inner membrane of the mitochondria, inserts iron into protoporphyrin IX to produce heme (14,15), which then reaches the cytosol to form the regulatory heme. Regulatory heme binds to the hemeregulatory motif in specific proteins.…”

mentioning

confidence: 99%

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

Atamna¹,

Boyle²

2006

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

272

279

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Amyloid-␤ peptide (A␤) is the toxic agent in Alzheimer's disease (AD), although the mechanism causing the neurodegeneration is not known. We previously proposed a mechanism in which excessive A␤ binds to regulatory heme, triggering functional heme deficiency (HD), causing the key cytopathologies of AD. We demonstrated that HD triggers the release of oxidants (e.g., H 2O2) from mitochondria due to the loss of complex IV, which contains heme-a. Now we add more evidence that A␤ binding to regulatory heme in vivo is the mechanism by which A␤ causes HD. Heme binds to A␤, thus preventing A␤ aggregation by forming an A␤-heme complex in a cell-free system. We suggest that this complex depletes regulatory heme, which would explain the increase in heme synthesis and iron uptake we observe in human neuroblastoma cells. The A␤-heme complex is shown to be a peroxidase, which catalyzes the oxidation of serotonin and 3,4-dihydroxyphenylalanine by H 2O2. Curcumin, which lowers oxidative damage in the brain in a mouse model for AD, inhibits this peroxidase. The binding of A␤ to heme supports a unifying mechanism by which excessive A␤ induces HD, causes oxidative damage to macromolecules, and depletes specific neurotransmitters. The relevance of the binding of regulatory heme with excessive A␤ for mitochondrial dysfunction and neurotoxicity and other cytopathologies of AD is discussed.curcumin ͉ heme deficiency ͉ mitochondria ͉ regulatory heme ͉ serotonin

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Accumulation of heme in mitochondria from rabbit reticulocytes with inhibited globin synthesis

Cited by 32 publications

References 9 publications

A role for heme in Alzheimer's disease: Heme binds amyloid β and has altered metabolism

A role for heme in Alzheimer's disease: Heme binds amyloid β and has altered metabolism

Molecular Characterization of a Newly Identified Heme-binding Protein Induced during Differentiation of urine Erythroleukemia Cells

Amyloid-β peptide binds with heme to form a peroxidase: Relationship to the cytopathologies of Alzheimer’s disease

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