title: Macrophage Akt1 Kinase-Mediated Mitophagy Modulates Apoptosis Resistance and Pulmonary Fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder with increasing incidence. Mitochondrial oxidative stress in alveolar macrophages is directly linked to pulmonary fibrosis. Mitophagy, the selective engulfment of dysfunctional mitochondria by autophagasomes, is important for cellular homeostasis and can be induced by mitochondrial oxidative stress. Here, we show Akt1 induced macrophage mitochondrial reactive oxygen species (ROS) and mitophagy. Mice harboring a conditional deletion of Akt1 in macrophages (Akt1(-/-)Lyz2-cre) and Park2(-/-) mice had impaired mitophagy and reduced active transforming growth factor-β1 (TGF-β1). Although Akt1 increased TGF-β1 expression, mitophagy inhibition in Akt1-overexpressing macrophages abrogated TGF-β1 expression and fibroblast differentiation. Importantly, conditional Akt1(-/-)Lyz2-cre mice and Park2(-/-) mice had increased macrophage apoptosis and were protected from pulmonary fibrosis. Moreover, IPF alveolar macrophages had evidence of increased mitophagy and displayed apoptosis resistance. These observations suggest that Akt1-mediated mitophagy contributes to alveolar macrophage apoptosis resistance and is required for pulmonary fibrosis development.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Larson-Casey
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ryan
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Birmingham Veterans Administration Medical Center, Birmingham, AL 35294, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA; Birmingham Veterans Administration Medical Center, Birmingham, AL 35294, USA. Electronic address: bcarter1@uab.edu.
authors.forename: A Brent
authors.initials: AB
authors.lastname: Carter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology*; D008168:Lung / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D051057:Proto-Oncogene Proteins c-akt