Mitochondrial DNA (mtDNA) contains 37 genes that encode 13 proteins, 22 tRNAs, and 2 rRNAs, which are involved in the synthesis of enzymes required for oxidative phosphorylation. Mitochondrial DNA is highly sensitive to oxidative damage (1), and studies have shown an association between mtDNA damage and oxidant-induced cell death (2). In a recent article in press (3) titled “Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs” in AJP-Lung Cellular and Molecular Physiology, Dr. Mark Gillespie and his team found interesting data that demonstrated that pulmonary exposure to bacteria, such as Pseudomonas aeruginosa, leads to oxidative mtDNA damage and the accumulation of mtDNA damage-associated molecular patterns (mtDNA DAMPs). These mtDNA DAMPs caused further damage to mtDNA integrity, increased vascular permeability, and propagated bacteria-induced lung injury. The study concluded by showing that the administration of a fusion protein that targets the DNA repair enzyme, Ogg1, blocked the deleterious effects of P. aeruginosa. This study was particularly interesting because it suggested that during infection, a feed-forward cycle of mtDNA DAMP formation and mtDNA damage culminates in acute lung injury. The clinical implications of this study are enormous, and it raises some interesting questions about the long-term management of patients with respiratory bacterial infections. Therefore, it may be possible to supplement antibiotics with agents that repair lung mtDNA to prevent the development of acute lung injury and acute respiratory distress syndrome. However, what still remains unanswered is the cell-type that mainly contributes to the formation of the mtDNA DAMPs, whether the DAMPs from one cell-type are equally damaging compared to the DAMPs from another cell-type, and if the repair of mtDNA of non-resident inflammatory cells would exacerbate the disease outcome and progression. These questions need to be furthered explored and would be of great interest.
Author: Dr. Saurabh Aggarwal MD. Ph.D., Instructor, Department of Anesthesiology, University of Alabama at Birmingham, AL
1. Grishko, V., Solomon, M., Wilson, G. L., LeDoux, S. P., and Gillespie, M. N. (2001) Am J Physiol Lung Cell Mol Physiol 280, L1300-1308
2. Grishko, V., Solomon, M., Breit, J. F., Killilea, D. W., Ledoux, S. P., Wilson, G. L., and Gillespie, M. N. (2001) FASEB J 15, 1267-1269
3. Kuck, J. L., Obiako, B. O., Gorodnya, O. M., Pastukh, V. M., Kua, J., Simmons, J. D., and Gillespie, M. N. (2015) Am J Physiol Lung Cell Mol Physiol, ajplung 00015 02015