Bioenergetic function is decreased in peripheral blood mononuclear cells of veterans with Gulf War Illness

• Published in: PloS one 2023-11, Vol.18 (11), p.e0287412-e0287412
• Main Authors: Meyer, Joel N, Pan, William K, Ryde, Ian T, Alexander, Thomas, Klein-Adams, Jacquelyn C, Ndirangu, Duncan S, Falvo, Michael J
• Format: Article
• Language: English
• Subjects: Acidification; Adenosine Triphosphate; Analysis; ATP; Bioenergetics; Biological warfare; Biological Warfare Agents; Biology and Life Sciences; Biometrics; Blood circulation; Bromides; Care and treatment; Case-Control Studies; Copy number; Correlation coefficient; Correlation coefficients; Damage detection; Demographics; Diagnosis; DNA damage; DNA, Mitochondrial; Electron transport; Energy; Energy Metabolism; Ethylenediaminetetraacetic acid; Exposure; Genomes; Glycolysis; Gulf War; Gulf War syndrome; Health aspects; Humans; Illnesses; Laboratory models; Leukocytes, Mononuclear; Military personnel; Mitochondria; Mitochondrial DNA; Monocytes; Observational studies; Oxidative phosphorylation; Oxygen consumption; Peripheral blood mononuclear cells; Permethrin; Persian Gulf Syndrome; Persian Gulf War; Pesticides; Phosphorylation; Physical Sciences; Protons; Pyridostigmine; Pyridostigmine Bromide; Remission (Medicine); Respiration; Respiratory function; Signs and symptoms; Social aspects; Veterans; War
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0287412

Gulf War Illness (GWI) is a major health problem for approximately 250,000 Gulf War (GW) veterans, but the etiology of GWI is unclear. We hypothesized that mitochondrial dysfunction is an important contributor to GWI, based on the similarity of some GWI symptoms to those occurring in some mitochondrial diseases; the plausibility that certain pollutants to which GW veterans were exposed affect mitochondria; mitochondrial effects observed in studies in laboratory models of GWI; and previous evidence of mitochondrial outcomes in studies in GW veterans. A primary role of mitochondria is generation of energy via oxidative phosphorylation. However, direct assessment of mitochondrial respiration, reflecting oxidative phosphorylation, has not been carried out in veterans with GWI. In this case-control observational study, we tested multiple measures of mitochondrial function and integrity in a cohort of 114 GW veterans, 80 with and 34 without GWI as assessed by the Kansas definition. In circulating white blood cells, we analyzed multiple measures of mitochondrial respiration and extracellular acidification, a proxy for non-aerobic energy generation; mitochondrial DNA (mtDNA) copy number; mtDNA damage; and nuclear DNA damage. We also collected detailed survey data on demographics; deployment; self-reported exposure to pesticides, pyridostigmine bromide, and chemical and biological warfare agents; and current biometrics, health and activity levels. We observed a 9% increase in mtDNA content in blood in veterans with GWI, but did not detect differences in DNA damage. Basal and ATP-linked oxygen consumption were respectively 42% and 47% higher in veterans without GWI, after adjustment for mtDNA amount. We did not find evidence for a compensatory increase in anaerobic energy generation: extracellular acidification was also lower in GWI (12% lower at baseline). A subset of 27 and 26 veterans returned for second and third visits, allowing us to measure stability of mitochondrial parameters over time. mtDNA CN, mtDNA damage, ATP-linked OCR, and spare respiratory capacity were moderately replicable over time, with intraclass correlation coefficients of 0.43, 0.44, 0.50, and 0.57, respectively. Other measures showed higher visit-to-visit variability. Many measurements showed lower replicability over time among veterans with GWI compared to veterans without GWI. Finally, we found a strong association between recalled exposure to pesticides, pyridostigmine bromide, and chemic