Thursday, September 25, 2008

Hypothesis: ME/CFS caused by dysregulation of hydrogen sulfide metabolism

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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

Research on H2S -- the gas that causes the characteristic smell of
rotten eggs -- dates to the 1700‚s 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 [1]. 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

Consistent with this finding, recent research on low levelH2S toxicity
points to increased formation of free radicals and depolarization
of the mitochondrial membrane, a condition that would
decrease ATP synthesis [2]. 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 [3].

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 [4]. 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.

[1] Blackstone Eric, Morrison Mike, Roth Mark B. H2S induces a suspended
animation-like state in mice. Science Magazine 2005;308(5721):518.
[2] Eghbal MA, Pennefather PS, O‚Brien PJ. H2S cytotoxicity mechanism involves
reactive oxygen species formation and mitochondrial depolarisation.
Toxicology 2004;203(13):6976. PMID: 15363583.
[3] Attene-Ramos MS, Wagner ED, Gaskins HR, Plewa MJ. Hydrogen sulfide induces
direct radical-associated DNA damage. Mol Cancer Res 2007 [PMID: 17475672].
[4] Maes M, Mihaylova I, Leunis JC. Increased serum IgA and IgM against LPS of
enterobacteria in chronic fatigue syndrome (CFS): indication for the
involvement of gram-negative enterobacteria in the etiology of CFS and for
the presence of an increased gut-intestinal permeability. J Affect Disord
2007;99(13):23740. PMID: 17007934

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