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PubMed: 26974230

Title
Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells.
Journal
American journal of respiratory cell and molecular biology
Volume
55
Issue
None
Pages
288-98
Date
2016-08-01
Authors
Alayash AI | Chintagari NR | Jana S

Evidence 5373be067e
JSON

Moreover, mitochondrial translocation of HO-1 can also lead to localized CO production as a result of heme degradation, thus inhibiting electron flow though mitochondrial electron transport chain complex IV (44).

a(CHEBI:"carbon monoxide") decreases complex(a(GO:"mitochondrial respiratory chain complex IV")) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

p(MGI:Hmox1) increases a(CHEBI:"carbon monoxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

Evidence 9b0ac06335
JSON

Exposure to Hb and its oxidized products increases heme overload on the AT1 cells. Heme overload induces the expression of HO-1 and iron-sequestering proteins, such as ferritin.

a(CHEBI:heme) increases p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

a(CHEBI:heme) increases p(MGI:Fth1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) increases a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

Evidence 4ca6810aeb
JSON

We also found that HbFe21 and HbFe31 activate NF-kB and mitogen-activated protein kinase pathways, as shown by phosphorylation of NF-kB p65 subunit and p44/42, respectively (Figure E3) as noted previously (31).

a(CHEBI:methemoglobin) increases act(a(MESH:"Mitogen-Activated Protein Kinases")) View Subject | View Object

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MeSH
Alveolar Epithelial Cells
Text Location
Results

p(HGNC:HBB) increases act(p(MGI:Nfkb1)) View Subject | View Object

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MeSH
Alveolar Epithelial Cells
Text Location
Results

Evidence 2946919820
JSON

Exposure to ferric Hb (HbFe31) induced a significant expression in HO-1 protein– (15.1761.04-fold) when compared with HbFe21 (9.3260.76-fold)- induced expression (Figure 2C).

a(CHEBI:methemoglobin) increases p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alveolar Epithelial Cells
Text Location
Results

Evidence d8b9802507
JSON

We found a significant enrichment of HO-1 in the mitochondrial, but not in the cytosolic fractions after exposure to HbFe21 and HbFe31 (Figures 3A and 3B).

a(CHEBI:methemoglobin) increases p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Mitochondria
Text Location
Results

p(HGNC:HBB) increases p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
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MeSH
Mitochondria
Text Location
Results

Evidence f51f3408c2
JSON

Similarly, HbFe31 induced a significant expression H-ferritin protein (60.4062.76-fold) when compared with a 25.25 (61.91)-fold induction by HbFe21 (Figure 2D).

a(CHEBI:methemoglobin) increases p(MGI:Fth1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alveolar Epithelial Cells
Text Location
Results

Evidence 66baa5e881
JSON

Exposure to HbFe21 and HbFe31 did not alter the expression of cytochrome c oxidase IV protein (Figure 3A).

a(CHEBI:methemoglobin) causesNoChange p(MGI:Cox4i1) View Subject | View Object

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MeSH
Mitochondria
Text Location
Results

p(HGNC:HBB) causesNoChange p(MGI:Cox4i1) View Subject | View Object

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MeSH
Mitochondria
Text Location
Results

Evidence 120bbbdeab
JSON

For example, HbFe41 (20 mM), but not HbFe31 or HbFe21, induced cytoskeletal reorganization, inflammation and disrupted barrier integrity in endothelial cells after 8 hours of incubation with the proteins.

a(MESH:ferrylhemoglobin) positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

a(MESH:ferrylhemoglobin) positiveCorrelation bp(HM:"cytoskeletal reorganization") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

bp(HM:"cytoskeletal reorganization") positiveCorrelation a(MESH:ferrylhemoglobin) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

path(MESH:Inflammation) positiveCorrelation a(MESH:ferrylhemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

Evidence 2786de1240
JSON

Exposure to HbFe41 caused a significant up-regulation of HO-1 within 12 hours when compared with HbFe21 and HbFe31 (Figures 4A and 4B).

a(MESH:ferrylhemoglobin) increases p(MGI:Hmox1) View Subject | View Object

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MeSH
Mitochondria
Text Location
Results

Evidence 2c37cd1a40
JSON

We found significant enrichment of HO-1 in mitochondrial fraction after exposure to HbFe31 and HbFe41 (Figure 4C).

a(MESH:ferrylhemoglobin) increases p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Mitochondria
Text Location
Results

Evidence 798085f8cd
JSON

Exposure to HbFe41 resulted in a drop in hyperpolarized cell percentage over untreated control, thus indicating a significant mitochondrial depolarization or compromised mitochondrial respiration.

a(MESH:ferrylhemoglobin) positiveCorrelation bp(GO:"mitochondrial depolarization") View Subject | View Object

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MeSH
Mitochondria
Text Location
Results

a(MESH:ferrylhemoglobin) negativeCorrelation bp(GO:"cellular respiration") View Subject | View Object

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Annotations
MeSH
Mitochondria
Text Location
Results

bp(GO:"cellular respiration") negativeCorrelation a(MESH:ferrylhemoglobin) View Subject | View Object

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Annotations
MeSH
Mitochondria
Text Location
Results

bp(GO:"mitochondrial depolarization") positiveCorrelation a(MESH:ferrylhemoglobin) View Subject | View Object

Appears in Networks:
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MeSH
Mitochondria
Text Location
Results

Evidence 726101899f
JSON

Subsequent RBC lysis leads to release of acellular Hb, which, in turn, damages the alveolar epithelial cells.

p(HGNC:HBB) positiveCorrelation path(MESH:Hemolysis) View Subject | View Object

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Annotations
MeSH
Alveolar Epithelial Cells
Text Location
Introduction

path(MESH:Hemolysis) positiveCorrelation p(HGNC:HBB) View Subject | View Object

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MeSH
Alveolar Epithelial Cells
Text Location
Introduction

Evidence 0549bff6e5
JSON

We found that Hpx effectively attenuated HO-1 induction by all redox forms of Hb.

p(MGI:Hpx) decreases p(MGI:Hmox1) View Subject | View Object

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MeSH
Mitochondria
Text Location
Results

Evidence 6bd518c73b
JSON

Hp attenuated HbFe21- and HbFe31-induced up-regulation of HO-1 and H-ferritin proteins (Figure 2B).

p(MGI:Hp) decreases p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alveolar Epithelial Cells
Text Location
Results

p(MGI:Hp) decreases p(MGI:Fth1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Alveolar Epithelial Cells
Text Location
Results

Evidence b09ced270a
JSON

Interestingly, Hp attenuated the HbFe21- and HbFe31-induced HO-1 expression in the mitochondria (Figures 3A and 3B).

p(MGI:Hp) decreases p(MGI:Hmox1) View Subject | View Object

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MeSH
Mitochondria
Text Location
Results

Evidence 890faf51b8
JSON

However, hemin or LPS-induced mitochondrial accumulation of HO-1 was associated with decreased mitochondrial heme content and reduced expression of heme-sensitive subunit I of complex IV with loss of activity (33).

p(MGI:Cox4i1) negativeCorrelation p(MGI:Hmox1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

p(MGI:Hmox1) negativeCorrelation p(MGI:Cox4i1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

Evidence 7d8e76acce
JSON

A recent study indicated that expression of HO-1 targeted to mitochondria attenuated oxidative stress (43).

p(MGI:Hmox1) decreases bp(MESH:"Oxidative Stress") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Discussion

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