New research suggests that mitochondrial dysfunction, not inflammation, drives the symptoms experienced by Veterans with Gulf War Syndrome.
Gulf War Illness (GWI), also called Gulf War Syndrome, is a multi-symptom health condition that has impacted 175,000 to 250,000 Veterans who served in the Persian Gulf War from 1990 to 1991.
GWI causes a cluster of symptoms, including fatigue, indigestion, headaches, joint pain, insomnia, skin problems, and memory impairment.
However, the root cause and mechanisms behind the illness have mystified doctors and scientists for decades. But a breakthrough occurred in 2022 when researchers found strong evidence that exposure to the chemical weapon sarin caused GWI. Sarin was likely released when United States troops bombed Iraqi chemical weapons production and storage facilities.
Still, scientists have had a long-standing belief that inflammation somehow played a role in the illness, although many people with GWI don't respond adequately to anti-inflammatory drugs.
New research suggests that inflammation is just a side effect of the real mechanism driving GWI — mitochondrial dysfunction.
In the study, published on July 12 in Scientific Reports, UC San Diego researchers obtained muscle biopsies from 36 participants to measure mitochondrial respiratory chain function (MRCF) levels. Of those, 19 had GWI, and 17 did not have the condition. The scientists also took blood samples to assess inflammatory markers and asked the Veterans with GWI to rate the severity of their symptoms.
The team found that the severity of the participants' GWI symptoms was significantly related to the level of mitochondrial dysfunction. Moreover, further analysis revealed that mitochondrial function plays a role in 17 of the 20 symptoms commonly associated with GWI.
However, only one of the 20 GWI symptoms met the criteria for inflammation.
Looking into this further, the scientist found that how severely mitochondria were impaired in converting fat to energy was strongly associated with the level of inflammation in the Veterans with GWI. This finding leads researchers to believe that mitochondrial dysfunction may be the reason why inflammation is higher in Veterans with the condition.
Notably, previous 2016 research suggests that sarin-like compounds induce mitochondrial dysfunction and apoptotic cell death in human astrocytoma cells.
In a news release, corresponding author Beatrice Golomb, M.D, Ph.D., a professor of medicine at UC San Diego School of Medicine, says, "Inflammation does appear to be linked to GWI, but our work suggests that it's actually a side effect of the primary issue, which is impaired cell energy."
The study authors explain that impaired cell energy caused by mitochondrial dysfunction could lead to many of the symptoms experienced by Veterans with GWI. For example, impaired sugar-fueled mitochondrial energy production could impact cognitive function, as the brain counts on sugar for energy.
Moreover, the researchers suggest these findings might help explain other health conditions linked to inflammation that fail to respond well to anti-inflammatory medications.
"This is the first time that direct evidence for the mitochondrial hypothesis of GWI has been reported," notes Golomb. "We hope that it will lead to improved treatment plans for the veterans who have long struggled with this mysterious illness."
- U.S. Department of Veteran Affairs. Gulf War Veterans.
- Environmental Health Perspectives. Evaluation of a Gene–Environment Interaction of PON1 and Low-Level Nerve Agent Exposure with Gulf War Illness: A Prevalence Case–Control Study Drawn from the U.S. Military Health Survey's National Population Sample.
- Disabled American Veterans. Gulf War Illness Symptoms Baffled Scientists. Until Now.
- Scientific Reports. Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity.
- The Journal of Toxicological Sciences. The sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate induces ER stress in human astrocytoma cells.