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Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis

Jennifer L Larson-Casey1, Jessy S Deshane1, Alan J Ryan2

  • 1Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Immunity
|February 28, 2016
PubMed

Insights

Akt1 protein triggers mitophagy in macrophages, a process linked to pulmonary fibrosis development. Inhibiting this pathway protects against lung fibrosis by reducing macrophage apoptosis resistance.

Area of Science:

  • Cell Biology
  • Immunology
  • Pulmonary Medicine

Background:

  • Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with rising incidence.
  • Mitochondrial oxidative stress in alveolar macrophages is a key factor in pulmonary fibrosis.
  • Mitophagy, the removal of damaged mitochondria, is crucial for cell health and can be triggered by oxidative stress.

Purpose of the Study:

  • To investigate the role of Akt1 in macrophage mitophagy and its contribution to pulmonary fibrosis.
  • To determine the relationship between Akt1, mitophagy, and transforming growth factor-beta 1 (TGF-β1) signaling in fibrosis.

Main Methods:

  • Utilized Akt1 conditional knockout mice (Akt1(-/-)Lyz2-cre) and Park2 knockout mice.
  • Assessed mitophagy, reactive oxygen species (ROS) production, TGF-β1 activation, fibroblast differentiation, and macrophage apoptosis.
  • Examined alveolar macrophages from IPF patients.

Main Results:

  • Akt1 was found to induce mitochondrial ROS and mitophagy in macrophages.
  • Impaired mitophagy in Akt1(-/-)Lyz2-cre and Park2(-/-) mice correlated with reduced TGF-β1 activation.
  • Akt1 overexpression increased TGF-β1, but mitophagy inhibition prevented this effect and subsequent fibroblast differentiation.
  • Akt1 deficiency or Parkin deficiency led to increased macrophage apoptosis and protection from pulmonary fibrosis.
  • IPF alveolar macrophages exhibited increased mitophagy and resistance to apoptosis.

Conclusions:

  • Akt1-mediated mitophagy in macrophages promotes apoptosis resistance.
  • This Akt1-driven mitophagy pathway is essential for the development of pulmonary fibrosis.
  • Targeting Akt1-mediated mitophagy may offer a therapeutic strategy for IPF.

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