title: The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis.
abstract: Convincing evidence has emerged demonstrating that impairment of mitochondrial function is critically important in regulating alveolar epithelial cell (AEC) programmed cell death (apoptosis) that may contribute to aging-related lung diseases, such as idiopathic pulmonary fibrosis (IPF) and asbestosis (pulmonary fibrosis following asbestos exposure). The mammalian mitochondrial DNA (mtDNA) encodes for 13 proteins, including several essential for oxidative phosphorylation. We review the evidence implicating that oxidative stress-induced mtDNA damage promotes AEC apoptosis and pulmonary fibrosis. We focus on the emerging role for AEC mtDNA damage repair by 8-oxoguanine DNA glycosylase (OGG1) and mitochondrial aconitase (ACO-2) in maintaining mtDNA integrity which is important in preventing AEC apoptosis and asbestos-induced pulmonary fibrosis in a murine model. We then review recent studies linking the sirtuin (SIRT) family members, especially SIRT3, to mitochondrial integrity and mtDNA damage repair and aging. We present a conceptual model of how SIRTs modulate reactive oxygen species (ROS)-driven mitochondrial metabolism that may be important for their tumor suppressor function. The emerging insights into the pathobiology underlying AEC mtDNA damage and apoptosis is suggesting novel therapeutic targets that may prove useful for the management of age-related diseases, including pulmonary fibrosis and lung cancer.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. seokjo.kim@northwestern.edu.|Division of Pulmonary & Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. seokjo.kim@northwestern.edu.
authors.forename: Seok-Jo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. p-cheresh@northwestern.edu.|Division of Pulmonary & Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. p-cheresh@northwestern.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Cheresh
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. renea.jablonski@northwestern.edu.|Division of Pulmonary & Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. renea.jablonski@northwestern.edu.
authors.forename: Renea P
authors.initials: RP
authors.lastname: Jablonski
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. D-Williams@northwestern.edu.|Division of Pulmonary & Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. D-Williams@northwestern.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA. d-kamp@northwestern.edu.|Division of Pulmonary & Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. d-kamp@northwestern.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
mesh_terms: D000375:Aging; D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial; D004195:Disease Models, Animal; D006147:Guanine / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D056566:Sirtuin 3
keywords: Sirtuin 3; alveolar epithelial cell; mitochondrial DNA damage; oxidative stress; pulmonary fibrosis