Tumor necrosis factor-α and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis

Naira Baregamian, Jun Song, C. Eric Bailey, John Papaconstantinou, B. Mark Evers, Dai H. Chung

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Background: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)α is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNFα/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. Results: We found (a) abundant tissue TNFα and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNFα/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNFα-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNFα-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNFα/ROS-induced intestinal epithelial cell injury; (e) TNFα induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNFα/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a late phenomenon. Methods: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNFα and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells were used to determine the effects of TNFα on mitochondrial function. Conclusions: Our findings suggest that TNFα induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC. Therapies directed against mitochondria/ ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NEC.

Original languageEnglish (US)
Pages (from-to)297-306
Number of pages10
JournalOxidative Medicine and Cellular Longevity
Volume2
Issue number5
DOIs
StatePublished - Nov 2009
Externally publishedYes

Fingerprint

MAP Kinase Kinase Kinase 5
Necrotizing Enterocolitis
Phosphorylation
JNK Mitogen-Activated Protein Kinases
Autophagy
Reactive Oxygen Species
Tumor Necrosis Factor-alpha
Epithelial Cells
Reactive ion etching
Mitochondria
Chemical activation
Apoptosis
Mitochondrial DNA
Wounds and Injuries
Oxidative stress
Mitochondrial Membrane Potential
Oxygen Consumption

Keywords

  • Apoptosis
  • ASK1
  • Intestinal epithelial cells
  • JNK
  • Mitochondrial membrane potential
  • Mitogen-activated protein kinases
  • Necrotizing enterocolitis
  • p38
  • TNFα

ASJC Scopus subject areas

  • Cell Biology
  • Aging
  • Biochemistry

Cite this

@article{722e0fc76f0e49d0805b57fac5926e91,
title = "Tumor necrosis factor-α and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis",
abstract = "Background: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)α is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNFα/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. Results: We found (a) abundant tissue TNFα and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNFα/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNFα-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNFα-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNFα/ROS-induced intestinal epithelial cell injury; (e) TNFα induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNFα/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a late phenomenon. Methods: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNFα and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells were used to determine the effects of TNFα on mitochondrial function. Conclusions: Our findings suggest that TNFα induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC. Therapies directed against mitochondria/ ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NEC.",
keywords = "Apoptosis, ASK1, Intestinal epithelial cells, JNK, Mitochondrial membrane potential, Mitogen-activated protein kinases, Necrotizing enterocolitis, p38, TNFα",
author = "Naira Baregamian and Jun Song and Bailey, {C. Eric} and John Papaconstantinou and Evers, {B. Mark} and Chung, {Dai H.}",
year = "2009",
month = "11",
doi = "10.4161/oxim.2.5.9541",
language = "English (US)",
volume = "2",
pages = "297--306",
journal = "Oxidative Medicine and Cellular Longevity",
issn = "1942-0900",
publisher = "Hindawi Publishing Corporation",
number = "5",

}

TY - JOUR

T1 - Tumor necrosis factor-α and apoptosis signal-regulating kinase 1 control reactive oxygen species release, mitochondrial autophagy and c-Jun N-terminal kinase/p38 phosphorylation during necrotizing enterocolitis

AU - Baregamian, Naira

AU - Song, Jun

AU - Bailey, C. Eric

AU - Papaconstantinou, John

AU - Evers, B. Mark

AU - Chung, Dai H.

PY - 2009/11

Y1 - 2009/11

N2 - Background: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)α is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNFα/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. Results: We found (a) abundant tissue TNFα and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNFα/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNFα-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNFα-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNFα/ROS-induced intestinal epithelial cell injury; (e) TNFα induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNFα/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a late phenomenon. Methods: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNFα and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells were used to determine the effects of TNFα on mitochondrial function. Conclusions: Our findings suggest that TNFα induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC. Therapies directed against mitochondria/ ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NEC.

AB - Background: Oxidative stress and inflammation may contribute to the disruption of the protective gut barrier through various mechanisms; mitochondrial dysfunction resulting from inflammatory and oxidative injury may potentially be a significant source of apoptosis during necrotizing enterocolitis (NEC). Tumor necrosis factor (TNF)α is thought to generate reactive oxygen species (ROS) and activate the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway. Hence, the focus of our study was to examine the effects of TNFα/ROS on mitochondrial function, ASK1-JNK/p38 cascade activation in intestinal epithelial cells during NEC. Results: We found (a) abundant tissue TNFα and ASK1 expression throughout all layers of the intestine in neonates with NEC, suggesting that TNFα/ASK1 may be a potential source (indicators) of intestinal injury in neonates with NEC; (b) TNFα-induced rapid and transient activation of JNK/p38 apoptotic signaling in all cell lines suggests that this may be an important molecular characteristic of NEC; (c) TNFα-induced rapid and transient ROS production in RIE-1 cells indicates that mitochondria are the predominant source of ROS, demonstrated by significantly attenuated response in mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells; (d) further studies with mitochondria-targeted antioxidant PBN supported our hypothesis that effective mitochondrial ROS trapping is protective against TNFα/ROS-induced intestinal epithelial cell injury; (e) TNFα induces significant mitochondrial dysfunction in intestinal epithelial cells, resulting in increased production of mtROS, drop in mitochondrial membrane potential (MMP) and decreased oxygen consumption; (f) although the significance of mitochondrial autophagy in NEC has not been unequivocally shown, our studies provide a strong preliminary indication that TNFα/ROS-induced mitochondrial autophagy may play a role in NEC, and this process is a late phenomenon. Methods: Paraffin-embedded intestinal sections from neonates with NEC and non-inflammatory condition of the gastrointestinal tract undergoing bowel resections were analyzed for TNFα and ASK1 expression. Rat (RIE-1) and mitochondrial DNA-depleted (RIE-1-ρ°) intestinal epithelial cells were used to determine the effects of TNFα on mitochondrial function. Conclusions: Our findings suggest that TNFα induces significant mitochondrial dysfunction and activation of mitochondrial apoptotic responses, leading to intestinal epithelial cell apoptosis during NEC. Therapies directed against mitochondria/ ROS may provide important therapeutic options, as well as ameliorate intestinal epithelial cell apoptosis during NEC.

KW - Apoptosis

KW - ASK1

KW - Intestinal epithelial cells

KW - JNK

KW - Mitochondrial membrane potential

KW - Mitogen-activated protein kinases

KW - Necrotizing enterocolitis

KW - p38

KW - TNFα

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U2 - 10.4161/oxim.2.5.9541

DO - 10.4161/oxim.2.5.9541

M3 - Article

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AN - SCOPUS:77953380853

VL - 2

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JO - Oxidative Medicine and Cellular Longevity

JF - Oxidative Medicine and Cellular Longevity

SN - 1942-0900

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ER -