Sequestration of mitochondrial iron by silica particle initiates a biological effect

Andrew J. Ghio, Haiyan Tong, Joleen M. Soukup, Lisa A. Dailey, Wan Yun Cheng, James M. Samet, Matthew J. Kesic, Philip A. Bromberg, Jennifer L. Turi, Daya Upadhyay, GR Scott Budinger, Gökhan M. Mutlu

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mitochondrial iron is a pivotal event mediating oxidant generation and biological effect. In vitro exposure of human bronchial epithelial cells to silica reduced intracellular iron, which resulted in increases in both the importer divalent metal transporter 1 expression and metal uptake. Diminished mitochondrial 57Fe concentrations following silica exposure confirmed particle sequestration of cell iron. Preincubation of cells with excess ferric ammonium citrate increased cell, nuclear, and mitochondrial metal concentrations and prevented significant iron loss from mitochondria following silica exposure. Cell and mitochondrial oxidant generation increased after silica incubation, but pretreatment with iron diminished this generation of reactive oxygen species. Silica exposure activated MAP kinases (ERK and p38) and altered the expression of transcription factors (nF-κB and NF-E2-related factor 2), proinflammatory cytokines (interleukin-8 and-6), and apoptotic proteins. All of these changes in indexes of biological effect were either diminished or inhibited by cell pretreatment with iron. Finally, percentage of neutrophils and total protein concentrations in an animal model instilled with silica were decreased by concurrent exposure to iron. We conclude that an initiating event in the response to particulate matter is a sequestration of cell and mitochondrial iron by endocytosed particle. The resultant oxidative stress and biological response after particle exposure are either diminished or inhibited by increasing the cell iron concentration.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume305
Issue number10
DOIs
StatePublished - Nov 15 2013

Fingerprint

Silicon Dioxide
Iron
Particulate Matter
Oxidants
Metals
NF-E2-Related Factor 2
Cohort Effect
p38 Mitogen-Activated Protein Kinases
Endocytosis
Interleukin-8
Inhalation
Interleukin-6
Reactive Oxygen Species
Mitochondria
Proteins
Oxidative Stress
Neutrophils
Transcription Factors
Animal Models
Epithelial Cells

Keywords

  • Inflammation
  • Oxidants
  • Particulate matter
  • Quartz

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Ghio, Andrew J. ; Tong, Haiyan ; Soukup, Joleen M. ; Dailey, Lisa A. ; Cheng, Wan Yun ; Samet, James M. ; Kesic, Matthew J. ; Bromberg, Philip A. ; Turi, Jennifer L. ; Upadhyay, Daya ; Budinger, GR Scott ; Mutlu, Gökhan M. / Sequestration of mitochondrial iron by silica particle initiates a biological effect. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013 ; Vol. 305, No. 10.
@article{e4a39bd0b4204fde8c0a1b81267b0233,
title = "Sequestration of mitochondrial iron by silica particle initiates a biological effect",
abstract = "Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mitochondrial iron is a pivotal event mediating oxidant generation and biological effect. In vitro exposure of human bronchial epithelial cells to silica reduced intracellular iron, which resulted in increases in both the importer divalent metal transporter 1 expression and metal uptake. Diminished mitochondrial 57Fe concentrations following silica exposure confirmed particle sequestration of cell iron. Preincubation of cells with excess ferric ammonium citrate increased cell, nuclear, and mitochondrial metal concentrations and prevented significant iron loss from mitochondria following silica exposure. Cell and mitochondrial oxidant generation increased after silica incubation, but pretreatment with iron diminished this generation of reactive oxygen species. Silica exposure activated MAP kinases (ERK and p38) and altered the expression of transcription factors (nF-κB and NF-E2-related factor 2), proinflammatory cytokines (interleukin-8 and-6), and apoptotic proteins. All of these changes in indexes of biological effect were either diminished or inhibited by cell pretreatment with iron. Finally, percentage of neutrophils and total protein concentrations in an animal model instilled with silica were decreased by concurrent exposure to iron. We conclude that an initiating event in the response to particulate matter is a sequestration of cell and mitochondrial iron by endocytosed particle. The resultant oxidative stress and biological response after particle exposure are either diminished or inhibited by increasing the cell iron concentration.",
keywords = "Inflammation, Oxidants, Particulate matter, Quartz",
author = "Ghio, {Andrew J.} and Haiyan Tong and Soukup, {Joleen M.} and Dailey, {Lisa A.} and Cheng, {Wan Yun} and Samet, {James M.} and Kesic, {Matthew J.} and Bromberg, {Philip A.} and Turi, {Jennifer L.} and Daya Upadhyay and Budinger, {GR Scott} and Mutlu, {G{\"o}khan M.}",
year = "2013",
month = "11",
day = "15",
doi = "10.1152/ajplung.00099.2013",
language = "English (US)",
volume = "305",
journal = "American Journal of Physiology",
issn = "1040-0605",
publisher = "American Physiological Society",
number = "10",

}

Ghio, AJ, Tong, H, Soukup, JM, Dailey, LA, Cheng, WY, Samet, JM, Kesic, MJ, Bromberg, PA, Turi, JL, Upadhyay, D, Budinger, GRS & Mutlu, GM 2013, 'Sequestration of mitochondrial iron by silica particle initiates a biological effect', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 305, no. 10. https://doi.org/10.1152/ajplung.00099.2013

Sequestration of mitochondrial iron by silica particle initiates a biological effect. / Ghio, Andrew J.; Tong, Haiyan; Soukup, Joleen M.; Dailey, Lisa A.; Cheng, Wan Yun; Samet, James M.; Kesic, Matthew J.; Bromberg, Philip A.; Turi, Jennifer L.; Upadhyay, Daya; Budinger, GR Scott; Mutlu, Gökhan M.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 305, No. 10, 15.11.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sequestration of mitochondrial iron by silica particle initiates a biological effect

AU - Ghio, Andrew J.

AU - Tong, Haiyan

AU - Soukup, Joleen M.

AU - Dailey, Lisa A.

AU - Cheng, Wan Yun

AU - Samet, James M.

AU - Kesic, Matthew J.

AU - Bromberg, Philip A.

AU - Turi, Jennifer L.

AU - Upadhyay, Daya

AU - Budinger, GR Scott

AU - Mutlu, Gökhan M.

PY - 2013/11/15

Y1 - 2013/11/15

N2 - Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mitochondrial iron is a pivotal event mediating oxidant generation and biological effect. In vitro exposure of human bronchial epithelial cells to silica reduced intracellular iron, which resulted in increases in both the importer divalent metal transporter 1 expression and metal uptake. Diminished mitochondrial 57Fe concentrations following silica exposure confirmed particle sequestration of cell iron. Preincubation of cells with excess ferric ammonium citrate increased cell, nuclear, and mitochondrial metal concentrations and prevented significant iron loss from mitochondria following silica exposure. Cell and mitochondrial oxidant generation increased after silica incubation, but pretreatment with iron diminished this generation of reactive oxygen species. Silica exposure activated MAP kinases (ERK and p38) and altered the expression of transcription factors (nF-κB and NF-E2-related factor 2), proinflammatory cytokines (interleukin-8 and-6), and apoptotic proteins. All of these changes in indexes of biological effect were either diminished or inhibited by cell pretreatment with iron. Finally, percentage of neutrophils and total protein concentrations in an animal model instilled with silica were decreased by concurrent exposure to iron. We conclude that an initiating event in the response to particulate matter is a sequestration of cell and mitochondrial iron by endocytosed particle. The resultant oxidative stress and biological response after particle exposure are either diminished or inhibited by increasing the cell iron concentration.

AB - Inhalation of particulate matter has presented a challenge to human health for thousands of years. The underlying mechanism for biological effect following particle exposure is incompletely understood. We tested the postulate that particle sequestration of cell and mitochondrial iron is a pivotal event mediating oxidant generation and biological effect. In vitro exposure of human bronchial epithelial cells to silica reduced intracellular iron, which resulted in increases in both the importer divalent metal transporter 1 expression and metal uptake. Diminished mitochondrial 57Fe concentrations following silica exposure confirmed particle sequestration of cell iron. Preincubation of cells with excess ferric ammonium citrate increased cell, nuclear, and mitochondrial metal concentrations and prevented significant iron loss from mitochondria following silica exposure. Cell and mitochondrial oxidant generation increased after silica incubation, but pretreatment with iron diminished this generation of reactive oxygen species. Silica exposure activated MAP kinases (ERK and p38) and altered the expression of transcription factors (nF-κB and NF-E2-related factor 2), proinflammatory cytokines (interleukin-8 and-6), and apoptotic proteins. All of these changes in indexes of biological effect were either diminished or inhibited by cell pretreatment with iron. Finally, percentage of neutrophils and total protein concentrations in an animal model instilled with silica were decreased by concurrent exposure to iron. We conclude that an initiating event in the response to particulate matter is a sequestration of cell and mitochondrial iron by endocytosed particle. The resultant oxidative stress and biological response after particle exposure are either diminished or inhibited by increasing the cell iron concentration.

KW - Inflammation

KW - Oxidants

KW - Particulate matter

KW - Quartz

UR - http://www.scopus.com/inward/record.url?scp=84887588575&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887588575&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00099.2013

DO - 10.1152/ajplung.00099.2013

M3 - Article

VL - 305

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 1040-0605

IS - 10

ER -