Hypothesis: Chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism Journal: Med Hypotheses. 2008 Sep 15. [Epub ahead of print] Author: Marian Dix Lemle, Washington, DC 20008, United States, Fax: +1 202 775 0045 NLM Citation: PMID: 18799269 Chronic fatigue syndrome (CFS), which is also known as myalgic encephalomyelitis (ME), is a debilitating, multi-system disease whose etiology is unclear, and for which there are as yet no reliable treatments. Here the hypothesis is advanced that the multi-system disturbances in CFS/ME are caused by disturbances in the homeostasis of endogenous hydrogen sulfide (H2S) and result in mitochondrial dysfunction. Research on H2S -- the gas that causes the characteristic smell of rotten eggs -- dates to the 1700s and has shown a remarkable range of effects in both animals and humans. At high concentrations, H2S has a variety of biological toxicities including being instantaneously deadly; at low concentrations some evidence suggests that H2S has beneficial effects and can act as an endogenous biological mediator the third such gaseous mediator discovered (after nitric oxide and carbon monoxide). The brain, pancreas and the gastrointestinal tract produce H2S. Endogenous H2S plays a role in regulating blood pressure, body temperature, vascular smooth muscle, cardiac function, cerebral ischemia, and in modulating the hypothalamus/pituitary/adrenal axis. It even has been called a "master metabolic regulator." Recent research has demonstrated that at low, non-toxic doses, exogenous H2S produces a reversible state of hibernation-like deanimation in mice, causing a decrease in core body temperature, an apnea-like sleep state, reduced heart and respiration rates, and a severe metabolic drop . These characteristics are not unlike the symptoms and extreme "de-animation" experienced by CFS/ME patients. Moreover, H2S affects biological networks that are disrupted by CFS including neurologic, endocrine and immunologic systems. Therefore, a plausible etiology of CFS is an increase in the activity of endogenous H2S, thereby inhibiting mitochondrial oxygen utilization. H2S and Mitochondria In this view, fatigue and the other CFS/ME symptoms could be due to diminished physiological and cellular energy due to reduction in the capacity of mitochondria to utilize oxygen and synthesize ATP. Specifically, H2S binds to the mitochondrial enzyme cytochrome c oxidase, which is part of Complex IV of the electron transport chain, and attenuates oxidative phosphorylation and ATP production. Consistent with this finding, recent research on low level H2S toxicity points to increased formation of free radicals and depolarization of the mitochondrial membrane, a condition that would decrease ATP synthesis . If poisoning renders mitochondria inefficient, one would expect cells to shift to anaerobic mechanisms, a shift that has been reported for CFS patients. Also consistent with this hypothesis is the fact that mitochondria are organelles descended from ancient eukaryotic sulfur-utilizing microbes. Thus, it is not surprising that they show a very high affinity for sulfide. Of course, H2S or sulfide may not directly affect mitochondria by binding to them. Genomic changes could mediate some of the effects of H2S. Some studies have found evidence for the involvement of the cytochrome c oxidase gene in CFS/ME. Also, investigators have found CFS abnormalities in genes related to fatty acid metabolism, apoptosis, mitochondrial membrane function, and protein production in mitochondria. Given a predisposing genetic background, H2S may lead to genomic instability or cumulative mutations in the mitochondrial DNA . Alternatively, the effects of H2S could be initially mediated by changes in the redox potential of cells or changes in their sulfur metabolism, especially in glutathione. Another possible mechanism is a direct effect of H2S on the immune system. Recent research indicates that exogenous hydrogen sulfide induces functional inhibition and cell death of cytotoxic lymphocyte subsets of CD8 (+) T cells and NK cells. Finally, H2S plays a pivotal role in both aerobic and non-anaerobic organisms as a signaling molecule. Bacteria in the gut both produce H2S and utilize it as a substrate alternative to oxygen. This is of particular relevance in the gastrointestinal tract, where unusually high levels of gram-negative bacteria, which increase intestinal permeability, have been found in patients with CFS/ME . In addition to bacteria, yeast, mold and other fungi also emit H2S. CFS/ME is a model disease for multisystem disturbance. It is my hypothesis that mitochondria, organelles required by every cell to sustain life, are unable to adequately utilize oxygen. This mitochondrial disturbance could be due to the combined effects of anaerobic conditions known to occur in CFS and associated low-level H2S toxicity. This increase in H2S alters fine signaling necessary for body homeostasis, and causes CFS. Understanding the role of H2S in the body, and, in particular, in mitochondrial function, may provide a unifying lens through which to view the diverse manifestations of this complex disease. References  Blackstone Eric, Morrison Mike, Roth Mark B. 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