Is inflammation a mitochondrial dysfunction-dependent event in fibromyalgia?

Abstract

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Both mitochondrial dysfunction and inflammation have been implicated in the pathophysiology of FM. We have investigated the possible relationship between mitochondrial dysfunction, oxidative stress, and inflammation in FM. We studied 30 women diagnosed with FM and 20 healthy women. Blood mononuclear cells (BMCs) from FM patients showed reduced level of coenzyme Q₁₀ (CoQ₁₀) and mtDNA contents and high level of mitochondrial reactive oxygen species (ROS) and serum tumor necrosis factor (TNF)-alpha and transcript levels. A significant negative correlation between CoQ₁₀ and TNF-alpha levels (r=-0.588; p<0.01), and a positive correlation between ROS and TNF-alpha levels (r=0.791; p<0.001) were observed accompanied by a significant correlation of visual analogical scale with serum TNF-alpha and transcript levels (r=0.4507; p<0.05 and r=0.7089; p<0.001, respectively). TNF-alpha release was observed in an in vitro (BMCs) and in vivo (mice) CoQ₁₀ deficiency model. Oral CoQ₁₀ supplementation restored biochemical parameters and induced a significant improvement in clinical symptoms (p<0.001). These results lead to the hypothesis that inflammation could be a mitochondrial dysfunction-dependent event implicated in the pathophysiology of FM in several patients indicating at mitochondria as a possible new therapeutic target.

FIG. 1.

Coenzyme Q₁₀ (CoQ₁₀) levels, mitochondrial reactive oxygen species (ROS) production, and tumor necrosis factor (TNF)-alpha levels in blood mononuclear cells (BMCs) from fibromyalgia (FM) patients and healthy control individuals. (A) CoQ₁₀ levels were measured by high-performance liquid chromatography, as described in Materials and Methods. (B) Reduced mtDNA contents in BMCs from FM patients compared with healthy controls. (C) Mitochondrial ROS production was analyzed in BMCs from controls and FM patients by flow cytometry as described in Material and Methods. (D) Serum TNF-alpha levels in FM and control patients were measured as described in Material and Methods. (E) tnf-alpha transcripts were analyzed by SYBR Green quantitative polymerase chain reaction as described in Materials and Methods. Data represent the mean±SD of three separate experiments. *p<0.001; **p<0.05 between controls and FM patients.

FIG. 2.

Correlations of: serum TNF-alpha versus CoQ₁₀(A), or versus mitochondrial ROS (B), and serum TNF-alpha and transcript tnf-alpha versus pain in FM patients (C and D). The correlations were established by calculating correlation coefficients.

FIG. 3.

Induced CoQ deficiency in vitro leads to mitochondrial ROS production and TNF-alpha release. 1 mM of P-aminobenzoate (PABA) induced partial CoQ₁₀ deficiency (A), and high levels of mitochondrial ROS production, being restored by antioxidants (B). CoQ deficiency provoked an important increment of TNF-alpha in the supernatant of cell cultures, counteracted by antioxidants (C). CoQ₁₀ produced a more significant protection than other antioxidants. Data represent the mean±SD of three separate experiments. *p<0.001 between control and PABA; **p<0.01 between PABA with absence or presence of CoQ₁₀; ***p<0.05 between presence of CoQ₁₀ or presence of BHA or N-acetylcysteine.

FIG. 4.

TNF-alpha release in a partial CoQ₁₀ depletion mice model. PABA was administered at a dose of 20 mg/kg/day for 15 days. (A) Levels of CoQ₉ and CoQ₁₀ measured in BMCs from mice treated with vehicle or PABA (mammalian species such as the mouse and the rat that have a relatively short lifespan primarily contain CoQ₉ and low levels of CoQ₁₀). Data represent the mean±SD of three separate experiments. *p<0.001 of CoQ₉ and CoQ₁₀ between vehicle or PABA. (B) TNF-alpha levels were measured in serum from mice treated with the vehicle or PABA. Data represent the mean±SD of three separate experiments. *p<0.001 between vehicle or PABA. (C) Correlation of TNF-alpha serum levels and pain in animal model. (n=5 per group).