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

1
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612, USA
2
Division of Pulmonary & Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Jaime M. Ross and Giuseppe Coppotelli
Int. J. Mol. Sci. 2015, 16(9), 21486-21519; https://doi.org/10.3390/ijms160921486
Received: 20 June 2015 / Revised: 29 July 2015 / Accepted: 26 August 2015 / Published: 7 September 2015
(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)
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. View Full-Text
Keywords: mitochondrial DNA damage; oxidative stress; Sirtuin 3; alveolar epithelial cell; pulmonary fibrosis mitochondrial DNA damage; oxidative stress; Sirtuin 3; alveolar epithelial cell; pulmonary fibrosis
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Kim, S.-J.; Cheresh, P.; Jablonski, R.P.; Williams, D.B.; Kamp, D.W. The Role of Mitochondrial DNA in Mediating Alveolar Epithelial Cell Apoptosis and Pulmonary Fibrosis. Int. J. Mol. Sci. 2015, 16, 21486-21519.

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