Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation. Academic Article uri icon

Overview

MeSH

  • Administration, Inhalation
  • Animals
  • Antioxidants
  • Cell Line, Tumor
  • Cytoprotection
  • Disease Models, Animal
  • Gases
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transfection

MeSH Major

  • Autophagy
  • Carbon Monoxide
  • Epithelial Cells
  • Hyperoxia
  • Mitochondria
  • Oxidative Stress
  • Reactive Oxygen Species
  • Respiratory Mucosa

abstract

  • Autophagy, an autodigestive process that degrades cellular organelles and protein, plays an important role in maintaining cellular homeostasis during environmental stress. Carbon monoxide (CO), a toxic gas and candidate therapeutic molecule, confers cytoprotection in animal models of acute lung injury. The mechanisms underlying CO-dependent lung cell protection and the role of autophagy in this process remain unclear. Here, we demonstrate that CO exposure time-dependently increased the expression and activation of the autophagic protein, microtubule-associated protein-1 light chain-3B (LC3B) in mouse lung, and in cultured human alveolar (A549) or human bronchial epithelial cells. Furthermore, CO increased autophagosome formation in epithelial cells by electron microscopy and green fluorescent protein (GFP)-LC3 puncta assays. Recent studies indicate that reactive oxygen species (ROS) play an important role in the activation of autophagy. CO up-regulated mitochondria-dependent generation of ROS in epithelial cells, as assayed by MitoSOX fluorescence. Furthermore, CO-dependent induction of LC3B expression was inhibited by N-acetyl-L-cysteine and the mitochondria-targeting antioxidant, Mito-TEMPO. These data suggest that CO promotes the autophagic process through mitochondrial ROS generation. We investigated the relationships between autophagic proteins and CO-dependent cytoprotection using a model of hyperoxic stress. CO protected against hyperoxia-induced cell death, and inhibited hyperoxia-associated ROS production. The ability of CO to protect against hyperoxia-induced cell death and caspase-3 activation was compromised in epithelial cells infected with LC3B-small interfering (si)RNA, indicating a role for autophagic proteins. These studies uncover a new mechanism for the protective action of CO, in support of potential therapeutic application of this gas.

publication date

  • October 2011

has subject area

  • Administration, Inhalation
  • Animals
  • Antioxidants
  • Autophagy
  • Carbon Monoxide
  • Cell Line, Tumor
  • Cytoprotection
  • Disease Models, Animal
  • Epithelial Cells
  • Gases
  • Humans
  • Hyperoxia
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins
  • Mitochondria
  • Oxidative Stress
  • RNA Interference
  • Reactive Oxygen Species
  • Respiratory Mucosa
  • Signal Transduction
  • Time Factors
  • Transfection

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3208612

Digital Object Identifier (DOI)

  • 10.1165/rcmb.2010-0352OC

PubMed ID

  • 21441382

Additional Document Info

start page

  • 867

end page

  • 873

volume

  • 45

number

  • 4