Oxidative Stress and Mitochondrial Injury in Chronic Multisymptom Conditions: From Gulf War Illness to Autism Spectrum Disorder

Abstract

Background: Overlapping chronic multisymptom illnesses (CMI) include Chronic Fatigue Syndrome (CFS), fibromyalgia, irritable bowel syndrome, multiple chemical sensitivity, and Gulf War illness (GWI), and subsets of autism spectrum disorder (ASD). GWI entails a more circumscribed set of experiences that may provide insights of relevance to overlapping conditions. Objectives: To consolidate evidence regarding a role for oxidative stress and mitochondrial dysfunction (OSMD), as primary mediators in CMI, using GWI as a departure point. Methods: Exposure relations, character, timecourse and multiplicity of symptoms, and objective correlates of GWI are compared to expectation for OSMD. Objective correlates of OSMD in GWI and overlapping conditions are examined. Discussion: OSMD is an expected consequence of known GWI exposures; is compatible with symptom characteristics observed; and accords with objective markers and health conditions linked to GWI, extending to autoimmune disease and infection. Emergent triangulating evidence directly supports OSMD in multisymptom "overlap" CMI conditions, with similarities to, and diagnosed at elevated rates in, GWI, suggesting a common role in each. Conclusions: GWI is compatible with a paradigm by which uncompensated exposure to oxidative/nitrative stressors accompanies and triggers mitochondrial dysfunction, cell energy compromise, and multiple downstream effects such as vulnerability to autoantibodies. This promotes a profile of protean symptoms with variable latency emphasizing but not confined to energy-demanding post-mitotic tissues, according with (and accounting for) known properties of multisystem overlap conditions. This advances understanding of GWI; health conditions attending GWI at elevated rates; and overlap conditions like CFS and ASD, providing prospects

Fluoroquinolone-induced serious, persistent, multisymptom adverse effects

“…The linking of other AEs following FQs to tendon pathology, the linking of tendon pathology (and FQ effects) to mitochondrial dysfunction in the literature,16 20 31 61–64 delayed mitochondrial dysfunction following FQ exposure (cell culture),31 delayed and widely variable latency to the onset of symptoms in mitochondrial dysfunction in humans (including those with heritable defects in the same kindred)65 and the known relation of mitochondrial dysfunction to the other FQ-affected domains, provide a strong case for causal occurrence. Moreover, principles have been outlined by which these processes may be expected to produce problems with a compatible profile, entailing variable latency of onset following exposure to a significant mitochondrial toxin, manifest in vulnerable individuals, affecting domains involving muscle–tendon, CNS, peripheral nervous system, gastrointestinal, autonomic, special sensory and other domains observed here 66 67…”

Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study

“…The exposure associations fit with symptom profiles and variable onset latency comport with OS-induced mitochondrial dysfunction, leading us to hypothesize a role for OS and mitochondrial dysfunction in GWI (Golomb, 2012) (see Figure 1 and Table 1). …”

“…It has benefited GWI-relevant symptoms such as fatigue (Judy, Stogsdill, & Folkers, 1998;Judy, Stogsdill, & Judy, 2002;Langsjoen & Folkers, 1993;Langsjoen, Langsjoen, Willis, & Folkers, 1997;Langsjoen, Langsjoen, Langsjoen, & Lucas, 2005), including chronic fatigue (Judy et al, 1998, Judy et al, 2002Langsjoen & Folkers, 1993;Langsjoen et al, 1997Langsjoen et al, , 2005)-a condition that arises at elevated rates in GWV (Gray et al, 2002;Steele, 2000;Unwin et al, 1999). Notably in one study, CoQ10 showed the greatest Exposures → OS Gulf War exposures promote OS-with particularly strong promotion for the chemical class particularly strongly linked to GWI (Golomb, 2012). Certain exposures/OS mediators (e.g., organophosphates) widely depress antioxidant systems (Altuntas, Delibas, & Sutcu, 2002) enhancing vulnerability to other oxidative stressors.…”

“…Indeed, many of the exposures that Gulf War veterans (GWV) experienced are known to be oxidative stressors (i.e., to promote injury, via reactive oxygen species or (ROS), to proteins, lipids, DNA, and RNA), and to confer toxicity through this means (Golomb, 2012). These include AChEi, specifically pyridostigmine bromide (a carbamate, used as a nerve agent pretreatment adjunct), organophosphate nerve agent, and organophosphate and carbamate pesticides) (Dandapani, Zachariah, Kavitha, Jeyaseelan, & Oommen, 2003;Golomb, 2008Golomb, , 2012Gupta, Milatovic, & Dettbarn, 2001a, 2001bHai, Varga, & Matkovics, 1995;John, Kale, Rathore, & Bhatnagar, 2001;Li, Shou, Borowitz, & Isom, 2001;Milatovic et al, 2006;Pazdernik, Emerson, Cross, Nelson, & Samson, 2001;Pena-Llopis et al, 2002;PenaLlopis, Ferrando, & Pena, 2003a, 2003bPoovala, Huang, & Salahudeen, 1999;Poovala, Kanji, Tachikawa, & Salahudeen, 1998); but also, if to a lesser degree, reactogenic vaccinations (Clapp et al, 2004); fuels, solvents, and exhausts (relevant to Gulf exposures of oil fires, tent heaters-petroleumrelated products) (Blaurock, Hippeli, Metz, & Elstner, 1992;Piotrowska, Dlugosz, & Pajak, 2002); metals and heavy metals (Monnet-Tschudi, Zurich, Boschat, Corbaz, & Honegger, 2006;Olivieri et al, 2002;Poliandri, Machiavelli, Quinteros, Cabilla, & Duvilanski, 2006;Risso-de Faverney, Orsini, de Sousa, & Rahmani, 2004;Wolf & Baynes, 2006) (relevant to depleted uranium, and aluminum in vaccine adjuvants); and radiation, as well as radioactivity (Karslioglu et al, 2005;Kim et al, 2006;Miura, 2004;Park et al, 2006;Shi, Wang, Wang, Zhang,...…”

Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness

“…28 One hypothesis of GWI suggests that toxicant exposures caused the chronic symptoms of GWI by directly damaging microtubules or mitochondria in a manner that the neurons and other affected cells are not equipped to selfrepair. 29,30 A second GWI hypothesis suggests that GW toxicants affected the brain in an additive manner to cause chronic, ongoing neuroinflammation. This chronic neuroinflammation is then thought to negatively affect microtubules and other cellular structures (including mitochondria), pathways, and mechanisms relevant to axonal transport.…”