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"Insight into the role of mitochondrial DNA damage and dysfunction in the military veterans with fatiguing multi-system illness"

by
Yang Chen
Cell Biology, Neuroscience and Physiology Track
B.S. 2009, Hunan Institute of Engineering, China
M.S. 2011, Hokkaido University, Japan


Thesis Advisor: Michael J. Falvo, Ph.D.
Assistant Professor
Department of Pharmacology, Physiology and Neuroscience

Tuesday, June 28, 2016
1:00 P.M., MSB Room H609


Abstract

Gulf War illness (GWI) is an unexplained multi-system illness not currently diagnosed by standard medical or laboratory tests that affects 26-32% of veterans who served the 1990-1991 Gulf War. Fatigue is the most common symptom, particularly fatigue occurring secondary to physical exertion, referred to as post-exertional malaise. Although the etiology of GWI remains unclear, multi-system symptoms may be a consequence of environmental exposures during deployment, such as pesticide and pyridostigmine bromide that could induce mitochondrial dysfunction and oxidative stress. Therefore, the purpose of our study is to identify whether mitochondrial DNA (mtDNA) damage and dysfunction are present in veterans with GWI, as well as their association with cardiopulmonary function. We recruited 21 veterans with GWI and 7 matched controls to participate in a two-day study (2 sessions, 24 hours apart) whereby participants provided blood samples, performed two maximal cycle ergometry tests, and completed health and symptom reports. Blood samples were used to quantify mtDNA damage and mtDNA copy number (mtDNAcn). Mitochondrial function was assessed via complex I and IV enzyme activities, and antioxidants system was evaluated by superoxide activity. Ventilatory, gas-exchange and heart rate responses during exercise were used to assess cardiopulmonary function. We observed higher mtDNAcn and mtDNA damage in veterans with GWI than controls (p = 0.001; p < 0.05). MtDNA damage was associated with lower mitochondrial complex I and IV activities (p < 0.01), and a similar trend in superoxide activity (p = 0.059). No differences were seen in exercise performance at peak exercise between exercise bouts; however, greater mtDNA damage was associated with lower oxygen consumption at ventilatory threshold during the 1st exercise bout (p < 0.05), as well as prolonged recovery of ventilation, carbon dioxide, and heart rate during 2nd exercise bout (p = 0.001; p = 0.056; p < 0.05). These results suggest individuals with higher mtDNA damage have impaired oxidative phosphorylation, lessened antioxidant capacity and poorer cardiopulmonary function. In conclusion, veterans with GWI exhibit mtDNA damage that is associated with impaired bioenergetics and cardiopulmonary performance. Therefore, mitochondrial dysfunction may be an underlying feature of GWI that is potentially modifiable through targeted therapies.


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