Upregulation and mitochondrial sequestration of hemoglobin occur in circulating leukocytes during critical illness, conferring a cytoprotective phenotype

Attila Brunyanszki, Katalin Erdelyi, Bartosz Szczesny, Gabor Olah, Reinaldo Salomao, David Herndon, Csaba Szabo

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation. However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (H2S). Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis). The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extracellular space via a CD163-dependent mechanism. Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from H2O2-induced cytotoxicity and mitochondrial DNA damage. Both burn injury and sepsis were associated with increased plasma levels of H2S. Incubation of mononuclear cells with H2S induced hemoglobin mRNA upregulation in PBMCs in vitro. Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by H2S. Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA. In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium. We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of H2S and other gaseous transmitters, oxidants and free radicals produced in critically ill patients.

Original languageEnglish (US)
Pages (from-to)666-675
Number of pages10
JournalMolecular Medicine
Volume21
DOIs
StatePublished - Aug 17 2015

Fingerprint

Critical Illness
Hemoglobins
Leukocytes
Up-Regulation
Phenotype
Blood Cells
Sepsis
Gasotransmitters
Hydrogen Sulfide
Messenger RNA
Globins
Mitochondrial Membrane Potential
Wounds and Injuries
Extracellular Space
Respiratory Rate
Mitochondrial DNA
Oxidants
DNA Damage
Oxidation-Reduction
Free Radicals

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Upregulation and mitochondrial sequestration of hemoglobin occur in circulating leukocytes during critical illness, conferring a cytoprotective phenotype. / Brunyanszki, Attila; Erdelyi, Katalin; Szczesny, Bartosz; Olah, Gabor; Salomao, Reinaldo; Herndon, David; Szabo, Csaba.

In: Molecular Medicine, Vol. 21, 17.08.2015, p. 666-675.

Research output: Contribution to journalArticle

@article{951dd75f7ef04f00bf62209b4eb32d21,
title = "Upregulation and mitochondrial sequestration of hemoglobin occur in circulating leukocytes during critical illness, conferring a cytoprotective phenotype",
abstract = "The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation. However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (H2S). Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis). The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extracellular space via a CD163-dependent mechanism. Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from H2O2-induced cytotoxicity and mitochondrial DNA damage. Both burn injury and sepsis were associated with increased plasma levels of H2S. Incubation of mononuclear cells with H2S induced hemoglobin mRNA upregulation in PBMCs in vitro. Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by H2S. Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA. In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium. We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of H2S and other gaseous transmitters, oxidants and free radicals produced in critically ill patients.",
author = "Attila Brunyanszki and Katalin Erdelyi and Bartosz Szczesny and Gabor Olah and Reinaldo Salomao and David Herndon and Csaba Szabo",
year = "2015",
month = "8",
day = "17",
doi = "10.2119/molmed.2015.00187",
language = "English (US)",
volume = "21",
pages = "666--675",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",

}

TY - JOUR

T1 - Upregulation and mitochondrial sequestration of hemoglobin occur in circulating leukocytes during critical illness, conferring a cytoprotective phenotype

AU - Brunyanszki, Attila

AU - Erdelyi, Katalin

AU - Szczesny, Bartosz

AU - Olah, Gabor

AU - Salomao, Reinaldo

AU - Herndon, David

AU - Szabo, Csaba

PY - 2015/8/17

Y1 - 2015/8/17

N2 - The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation. However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (H2S). Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis). The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extracellular space via a CD163-dependent mechanism. Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from H2O2-induced cytotoxicity and mitochondrial DNA damage. Both burn injury and sepsis were associated with increased plasma levels of H2S. Incubation of mononuclear cells with H2S induced hemoglobin mRNA upregulation in PBMCs in vitro. Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by H2S. Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA. In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium. We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of H2S and other gaseous transmitters, oxidants and free radicals produced in critically ill patients.

AB - The classical role of hemoglobin in the erythrocytes is to carry oxygen from the lungs to the tissues via the circulation. However, hemoglobin also acts as a redox regulator and as a scavenger of the gaseous mediators nitric oxide (NO) and hydrogen sulfide (H2S). Here we show that upregulation of hemoglobin (α, β and δ variants of globin proteins) occurs in human peripheral blood mononuclear cells (PBMCs) in critical illness (patients with severe third-degree burn injury and patients with sepsis). The increase in intracellular hemoglobin concentration is a result of a combination of enhanced protein expression and uptake from the extracellular space via a CD163-dependent mechanism. Intracellular hemoglobin preferentially localizes to the mitochondria, where it interacts with complex I and, on the one hand, increases mitochondrial respiratory rate and mitochondrial membrane potential, and on the other hand, protects from H2O2-induced cytotoxicity and mitochondrial DNA damage. Both burn injury and sepsis were associated with increased plasma levels of H2S. Incubation of mononuclear cells with H2S induced hemoglobin mRNA upregulation in PBMCs in vitro. Intracellular hemoglobin upregulation conferred a protective effect against cell dysfunction elicited by H2S. Hemoglobin uptake also was associated with a protection from, and induced the upregulation of, HIF-1α and Nrf2 mRNA. In conclusion, PBMCs in critical illness upregulate their intracellular hemoglobin levels by a combination of active synthesis and uptake from the extracellular medium. We propose that this process serves as a defense mechanism protecting the cell against cytotoxic concentrations of H2S and other gaseous transmitters, oxidants and free radicals produced in critically ill patients.

UR - http://www.scopus.com/inward/record.url?scp=84950243985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84950243985&partnerID=8YFLogxK

U2 - 10.2119/molmed.2015.00187

DO - 10.2119/molmed.2015.00187

M3 - Article

VL - 21

SP - 666

EP - 675

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

ER -