Mark N. Gillespie, Ph.D.
SAMSF-Locke Endowed Professor and Chair
USA Department of Pharmacology
Ph.D.: University of Kentucky
Post-doctoral: University of Colorado
Phone: (251) 460-6497
Research in the Gillespie laboratory focuses on defining novel biological roles of oxidative injury or modification to the two cellular genomes, mitochondrial (mt) and nuclear DNA, in governing the life and death of lung cells. One series of studies tests the idea that mtDNA functions as a "sentinel" molecule in which excessive damage caused by toxic oxygen radicals serves to activate cell death pathways. In an extension of this idea, we also are exploring the prospect that mtDNA repair pathways could emerge as isolated targets for pharmacologic intervention in acute lung injury. In contrast to oxidative damage to mtDNA, which occurs in the setting of toxicity, oxidants generated in the context of normal cell signaling do not alter mitochondrial DNA integrity, but surprisingly cause sequence-specific base modifications in nuclear genes. Because these oxidative modifications are clustered in promoter regions of inducible genes, our second major project tests the idea that oxidative DNA modifications accompanying physiological signals modify the topography and protein binding of functionally important DNA sequences and thereby influence gene regulation. This general hypothesis is tested experimental systems ranging in complexity from cultured lung cells to human lung tissue specimens from patients with COPD, idiopathic pulmonary hypertension, and other pulmonary disorders. These studies are significant because they have identified a new level of oxidant regulation of cell function at the level of the genome, and perhaps more importantly, because they point to links between normal cell signaling and somatic mutation underlying both malignant and non-malignant lung diseases.
Simmons JD, Lee Y-, Mulekar S, Kuck JL, Brevard SB, Gonzalez RP, et al. Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects. Ann Surg. 2013;258(4):591-6.
Gillespie MN, Al-Mehdi A-, McMurtry IF. Mitochondria in hypoxic pulmonary vasoconstriction: Potential importance of compartmentalized reactive oxygen species signaling. American Journal of Respiratory and Critical Care Medicine. 2013;187(4):338-40.
Hashizume M, Mouner M, Chouteau JM, Gorodnya OM, Ruchko MV, Potter BJ, et al. Mitochondrial-targeted DNA repair enzyme 8-oxoguanine DNA glycosylase 1 protects against ventilator-induced lung injury in intact mice. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013;304(4):L287-97.
Gebb SA, Decoux A, Waggoner A, Wilson GL, Gillespie MN. Mitochondrial DNA damage mediates hyperoxic dysmorphogenesis in rat fetal lung explants. Neonatology. 2013;103(2):91-7. Published online 2012 November 15. doi: 10.1159/000342632
Al-Mehdi A-, Pastukh VM, Swiger BM, Reed DJ, Patel MR, Bardwell GC, et al. Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci Signal. 2012 Jul 3;5(231):ra47. doi: 10.1126/scisignal.2002712.
Chouteau JM, Obiako B, Gorodnya OM, Pastukh VM, Ruchko MV, Wright AJ, et al. Mitochondrial DNA integrity may be a determinant of endothelial barrier properties in oxidant-challenged rat lungs. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011;301(6):L892-8.
Pastukh, V.M., M.V. Ruchko, G.C. Bardwell, R.M. Tuder and M.N. Gillespie. Oxidative DNA damage in lung tissue from patients with chronic obstructive pulmonary disease is clustered in functionally-significant sequences. Int J COPD. 6: 209-17, 2011.
Ruchko MV, Gorodnya OM, Zuleta A, Pastukh VM, Gillespie MN. The DNA glycosylase Ogg1 defends against oxidant-induced mtDNA damage and apoptosis in pulmonary artery endothelial cells. Free Radical Biology and Medicine. 2011;50(9):1107-13.
Ruchko MV, Gorodnya OM, Pastukh VM, Swiger BM, Middleton NS, Wilson GL, et al. Hypoxia-induced oxidative base modifications in the VEGF hypoxia-response element are associated with transcriptionally active nucleosomes. Free Radical Biology and Medicine. 2009;46(3):352-9.
Pastukh V, Ruchko M, Gorodnya O, Wilson GL, Gillespie MN. Sequence-specific oxidative base modifications in hypoxia-inducible genes. Free Radical Biology and Medicine. 2007;43(12):1616-26.
Ziel KA, Grishko V, Campbell CC, Breit JF, Wilson GL, Gillespie MN. Oxidants in signal transduction: Impact on DNA integrity and gene expression. FASEB Journal. 2005;19(3):387-94.
Ruchko M, Gorodnya O, LeDoux SP, Alexeyev MF, Al-Mehdi A-, Gillespie MN. Mitochondrial DNA damage triggers mitochondrial dysfunction and apoptosis in oxidant-challenged lung endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2005 Mar;288(3):L530-5. Epub 2004 Nov 24.
Ziel KA, Campbell CC, Wilson GL, Gillespie MN. Ref-1/Ape is critical for formation of the hypoxia-inducible transcriptional complex on the hypoxic response element of the rat pulmonary artery endothelial cell VEGF gene. FASEB Journal. 2004;18(9):986-8.
Dobson AW, Grishko V, Ledoux SP, Kelley MR, Wilson GL, Gillespie MN. Enhanced mtDNA repair capacity protects pulmonary artery endothelial cells from oxidant-mediated death. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2002;283(1 27-1):L205-10.
Grishko V, Solomon M, Wilson GL, LeDoux SP, Gillespie MN. Oxygen radical-induced mitochondrial DNA damage and repair in pulmonary vascular endothelial cell phenotypes. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2001;280(6 24-6):L1300-8.