Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cells, Cultured
  • Dynamins
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Necrosis
  • Protein Kinases
  • Quinazolinones
  • Smoke
  • Tobacco
  • Ubiquitin-Protein Ligases

MeSH Major

  • Apoptosis
  • Mitochondrial Degradation
  • Pulmonary Disease, Chronic Obstructive

abstract

  • The pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear, but involves loss of alveolar surface area (emphysema) and airway inflammation (bronchitis) as the consequence of cigarette smoke (CS) exposure. Previously, we demonstrated that autophagy proteins promote lung epithelial cell death, airway dysfunction, and emphysema in response to CS; however, the underlying mechanisms have yet to be elucidated. Here, using cultured pulmonary epithelial cells and murine models, we demonstrated that CS causes mitochondrial dysfunction that is associated with a reduction of mitochondrial membrane potential. CS induced mitophagy, the autophagy-dependent elimination of mitochondria, through stabilization of the mitophagy regulator PINK1. CS caused cell death, which was reduced by administration of necrosis or necroptosis inhibitors. Genetic deficiency of PINK1 and the mitochondrial division/mitophagy inhibitor Mdivi-1 protected against CS-induced cell death and mitochondrial dysfunction in vitro and reduced the phosphorylation of MLKL, a substrate for RIP3 in the necroptosis pathway. Moreover, Pink1(-/-) mice were protected against mitochondrial dysfunction, airspace enlargement, and mucociliary clearance (MCC) disruption during CS exposure. Mdivi-1 treatment also ameliorated CS-induced MCC disruption in CS-exposed mice. In human COPD, lung epithelial cells displayed increased expression of PINK1 and RIP3. These findings implicate mitophagy-dependent necroptosis in lung emphysematous changes in response to CS exposure, suggesting that this pathway is a therapeutic target for COPD.

publication date

  • September 2014

has subject area

  • Animals
  • Apoptosis
  • Cells, Cultured
  • Dynamins
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria
  • Mitochondrial Degradation
  • Necrosis
  • Protein Kinases
  • Pulmonary Disease, Chronic Obstructive
  • Quinazolinones
  • Smoke
  • Tobacco
  • Ubiquitin-Protein Ligases

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4151233

Digital Object Identifier (DOI)

  • 10.1172/JCI74985

PubMed ID

  • 25083992

Additional Document Info

start page

  • 3987

end page

  • 4003

volume

  • 124

number

  • 9