The role of mitochondrial DNA in mediating alveolar epithelial cell apoptosis and pulmonary fibrosis

Seok Jo Kim, Paul Cheresh, Renea P. Jablonski, David B. Williams, David W. Kamp*

*Corresponding author for this work

Research output: Contribution to journalReview article

47 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)21486-21519
Number of pages34
JournalInternational journal of molecular sciences
Volume16
Issue number9
DOIs
StatePublished - Sep 7 2015

Keywords

  • Alveolar epithelial cell
  • Mitochondrial DNA damage
  • Oxidative stress
  • Pulmonary fibrosis
  • Sirtuin 3

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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