Mitochondrial dysfunctions in Myalgic Encephalomyelitis / chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) is classified by the World Health Organization as a disorder of the central nervous system. ME/cfs is an neuro-immune disorder accompanied by chronic low-grade inflammation, increased levels of oxidative and nitrosative stress (O&NS), O&NS-mediated damage to fatty acids, DNA and proteins, autoimmune reactions directed against neoantigens and brain disorders. Mitochondrial dysfunctions have been found in ME/cfs, e.g. lowered ATP production, impaired oxidative phosphorylation and mitochondrial damage. This paper reviews the pathways that may explain mitochondrial dysfunctions in ME/cfs. Increased levels of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, and elastase, and increased O&NS may inhibit mitochondrial respiration, decrease the activities of the electron transport chain and mitochondrial membrane potential, increase mitochondrial membrane permeability, interfere with ATP production and cause mitochondrial shutdown. The activated O&NS pathways may additionally lead to damage of mitochondrial DNA and membranes thus decreasing membrane fluidity. Lowered levels of antioxidants, zinc and coenzyme Q10, and ω3 polyunsaturated fatty acids in ME/cfs may further aggravate the activated immuno-inflammatory and O&NS pathways. Therefore, it may be concluded that immuno-inflammatory and O&NS pathways may play a role in the mitochondrial dysfunctions and consequently the bioenergetic abnormalities seen in patients with ME/cfs. Defects in ATP production and the electron transport complex, in turn, are associated with an elevated production of superoxide and hydrogen peroxide in mitochondria creating adaptive and synergistic damage. It is argued that mitochondrial dysfunctions, e.g. lowered ATP production, may play a role in the onset of ME/cfs symptoms, e.g. fatigue and post exertional malaise, and may explain in part the central metabolic abnormalities observed in ME/cfs, e.g. glucose hypometabolism and cerebral hypoperfusion.

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

“…These factors are associated with PDK (22) and SIRT4 (47) in the regulation of oxidative metabolism. Such signaling pathways involve factors previously linked to ME/CFS, such as reactive oxygen species associated with signaling and mitochondrial dysfunction (48), and nitric oxide related to endothelial dysfunction, which has been demonstrated in ME/CFS (27). AMPK activates the endothelial nitric oxide synthase enzyme (eNOS) (49), and corrupted AMPK signaling may be a mechanism in endothelial dysfunction.…”

Effects of N-butylphthalide on the activation of Keap1/Nrf-2 signal pathway in rats after carbon monoxide poisoning

“…Its dysfunction will lead to cell disorders of energy supply, and ultimately result in cell apoptosis or death. The decreased mitochondrial membrane potential (MMP) is an early event of apoptosis, and the disappearance of MMP is often regarded as a symbol of irreversible cell death process (Zhang et al, 2015;Morris and Maes, 2014). By flow cytometry, Guratowska et al (2010) found significantly increased apoptosis of the lymphocytes correlated highly with the COpoisoning severity, but did not depend on hypoxia.…”

Association of biomarkers with health-related quality of life and history of stressors in myalgic encephalomyelitis/chronic fatigue syndrome patients

“…The definitions of ME/CFS do not use biological markers. Several body systems such as the muscular and nervous systems are affected in a context of neuro-immune alterations and chronic low-grade inflammation [3–6]. The etiology of ME/CFS is unknown, and its pathogenesis appears to be multifactorial, various stressors being repeatedly reported in the medical history of these patients, notably an intense sport practice, severe infections, and/or emotional stress [7, 8].…”