The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis

Our plain-English summary of The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis, by S.J. Kim, P. Cheresh, R.P. Jablonski, et al (International Journal of Molecular Sciences, 2015).

The study

• Authors: S.J. Kim, P. Cheresh, R.P. Jablonski, D.B. Williams, D.W. Kamp
• Journal: International Journal of Molecular Sciences
• Published: 2015;16(9):21486-519
• Type of article: Review
• Cited by: 101 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This article was a review, not a new study. The authors summarized published laboratory, animal and human research on damage to mitochondrial DNA (the small set of genes inside the cell's energy-producing mitochondria) in alveolar epithelial cells, which line the lung's air sacs. The question was whether this damage may lead to the death of those cells and to lung scarring (pulmonary fibrosis). They focused on asbestosis, the lung fibrosis that follows asbestos exposure. The review described the group's own earlier research. In cell studies, asbestos fibers taken up by these cells were followed by iron-derived reactive oxygen species, mitochondrial DNA damage and cell death. Mice lacking the DNA-repair enzyme OGG1 were more prone to pulmonary fibrosis after asbestos exposure than normal mice. The asbestos used in that mouse work was crocidolite. The review also covered research on the proteins ACO-2 and SIRT3. The authors concluded that this DNA damage may be important in promoting fibrosis-related signaling in IPF and asbestosis. They stated that how these findings translate into disease awaits further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research
• Who was studied: No new subjects. The review covered previously published cell, animal (mainly mouse and rat) and human studies, concentrating on alveolar epithelial cells of the lung
• Exposure: Oxidative stress, with a focus on asbestos exposure and asbestosis. Crocidolite asbestos was used in the authors' earlier mouse study. Bleomycin and silica models of fibrosis were also discussed
• Main results:
  • The review summarized the authors' group's earlier findings in alveolar epithelial cells. After asbestos fibers were taken up by the cells, iron-derived reactive oxygen species, mitochondrial DNA damage and mitochondria-driven cell death followed
  • The review cited the group's earlier report that, in alveolar epithelial cells, oxidative stress (asbestos or hydrogen peroxide) damaged mitochondrial DNA more than nuclear DNA, both in vitro and in vivo
  • The review described the group's earlier mouse study. Mice lacking OGG1 were more prone to pulmonary fibrosis after asbestos exposure than wild-type mice. The authors attributed this in part to increased mitochondrial DNA damage and cell death in alveolar epithelial cells
  • In that mouse study, lung cells from OGG1-deficient mice had more mitochondrial DNA damage, less ACO-2 and more p53 at baseline. These changes increased after three weeks of crocidolite asbestos exposure
  • The authors described an earlier finding from their group: OGG1 protected the mitochondrial enzyme ACO-2 from oxidative breakdown and thereby preserved mitochondrial DNA
  • The review cited studies by other investigators reporting raised mitochondrial Rac-1 levels in alveolar macrophages from patients with asbestosis
• The authors' conclusion: The authors concluded that damage to mitochondrial DNA in alveolar epithelial cells after oxidative or environmental stress may be important in promoting fibrosis-related signaling, as in IPF, asbestosis and other fibrotic lung diseases
• Limitations the authors state:
  • The authors stated that the role of OGG1, ACO-2 and SIRT3 inducers, and how this translates into disease, awaits further study
  • The authors stated that the significance in humans of OGG1 and ACO-2 for preventing pulmonary fibrosis still needs to be assessed
  • The authors stated that it is unknown whether small-molecule sirtuin inducers protect alveolar epithelial cells

Topics

Medical terms in this study, explained in our Lexicon: Apoptosis, Pulmonary Fibrosis, Idiopathic, Asbestos Exposure, Oxidative Stress, Reactive Oxygen Species (ROS), Lung Cancer.

Related studies

• SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis — R.P. Jablonski, S.J. Kim, et al. (2017)
• Mitochondria-targeted Ogg1 and aconitase-2 prevent oxidant-induced mitochondrial DNA damage in alveolar epithelial cells — S.J. Kim, P. Cheresh, et al. (2014)
• Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage — S.J. Kim, P. Cheresh, et al. (2016)
• Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice — P. Cheresh, L. Morales-Nebreda, et al. (2015)
• Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response — D.W. Kamp, G. Liu, et al. (2013)
• The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes — P. Cheresh, S.J. Kim, et al. (2020)

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