The main findings of the present study were twofold. First, we observed that patients suffering from FM exhibited impaired mitochondrial functionality compared to apparent healthy individuals. Among FM patients, those with a severe clinical presentation (FSS ≥ 20) demonstrated even worse mitochondrial functionality (lower BHI). Second, we identified a negative correlation only between BHI and WPI (a parameter describing musculoskeletal pain), and not between BHI and SSS. Considering that SSS reflects symptoms related to the psychological and functional domains (e.g., fatigue, sleep disturbance, cognitive symptoms, headache, abdominal pain or cramps, and depression), we hypothesize that the reduced mitochondrial functionality in FM patients primarily reflects musculoskeletal impairment rather than central nervous system involvement. The finding of a lower BHI in patients with positive ANA may suggest a role of these antibodies in mitochondrial function impairment, although the small sample size does not allow definitive conclusions. A study specifically designed to investigate the role of autoantibodies in mitochondrial function of patients with fibromyalgia syndrome will provide valuable insights into this field.
The choice of evaluating mitochondrial function in PBMCs and using them as a surrogate biomarker to assess fibromyalgia severity can be justified by the following evidence: a) PBMC mitochondrial respiration correlates with walking speed in older human adults (22) and with heart and skeletal muscle mitochondrial function in nonhuman primates (16); b) markers of PBMC mitochondrial content (i.e., PGC1α, cytochrome c oxidase subunit IV and mitochondrial NADH dehydrogenase subunit appeared to reflect training status in humans (17); c) high levels of mitochondrial reactive oxygen species and low levels of citrate synthase, a mitochondrial matrix protein whose activity correlates with mitochondrial mass, have been described in PBMCs of FM patients (23); d) when the analysis of mitochondrial function was tested in skin biopsies of fibromyalgia syndrome patients, this was similar to the one detected in PBMCs (24); e) lipid peroxidation levels, one of the consequences of reactive oxygen species overproduction, are better associated to clinical symptoms in FM when measured in PBMCs than in plasma (25).
Regarding the hypothesis that assessing mitochondrial function in PBMCs could serve as a surrogate marker of fibromyalgia syndrome severity, our findings align with the literature for similar clinical conditions. Deficits in mitochondrial function have been linked to chronic pain, and approximately 70% of patients with heritable mitochondrial diseases suffer from chronic pain (26). Impairment in mitochondrial basal respiration, extracellular acidification rate and ATP-linked OCR have been reported in patients suffering from chronic pain (27). Mitochondria play a role in pain resolution. For instance, macrophages can control the resolution of inflammatory pain by transferring mitochondria to sensory neurons (28). Proper regulation of mitochondrial activity appears crucial to prevent the transition from acute to chronic pain. Notably, compared to age- and sex-matched controls, PBMCs from fibromyalgia syndrome patients showed significantly lower mitochondrial coupling efficiency. Large-scale proteomics studies revealed altered mitochondrial metabolism, centered on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels (18).
The importance of mitochondria dysfunctionality in fatigue onset has been further highlighted by the ability to use mitochondrial electron transport chain gene expression to distinguish between individuals with systemic sclerosis and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) from non-fatigued patients. In this study, the presence of fatigue was associated with a specific gene expression pattern (i.e., reduced expression of mitochondrially encoded genes ND4 and CyB, and increased expression of nuclear gene Cox7C and ND4 and CyB expression). These expression changes were also correlated with disease severity, providing a distinct mitochondrial signature for systemic sclerosis patients with ME/CFS (29).
Mitochondrial dysfunction has also been implicated in neuropathic pain. In a murine model induced by chronic constriction injury, various mitochondrial genes and mtDNA copy number were decreased, emphasizing the importance of impaired mitochondrial biogenesis and function in neuropathic pain (30).
Furthermore, mitochondrial function may be linked to alterations in neurotransmitter release, including those involved in pain perception. This connection could contribute to the hypersensitivity to pain experienced by patients with fibromyalgia (31, 32).
Although the relationship between FM and mitochondrial dysfunction remains an active area of research, accumulating evidence suggests that mitochondrial dysfunction may play a role in the development and maintenance of fibromyalgia symptoms. Notably, a study investigating muscle energetics performance in a large cohort of older adults found that lower skeletal muscle energetics were associated with more severe performance fatigability (33). Interestingly, mitochondria ultrastructural alterations may underlie muscle fatigue. An analysis of murine fibers, particularly the fast-twitch type IIB/IIX fibers prone to fatigue, revealed elongated mitochondrial constrictions in response to fatigue. This effect was accompanied by elevated phosphorylation of Drp1, a key regulator of the fission (34).
Whether the mitochondrial imbalance is the cause, or a consequence of this disease remains an open question (35). However, we propose mitochondrial dysfunction, and BHI in particular, as a biomarker of fibromyalgia syndrome severity that may support clinicians in the diagnosis of a disease that is still today underestimated and underdiagnosed also due to the absence of validated biomarkers. In addition, mitochondrial dysfunction could serve as a therapeutic target in a disease where pathogenic mechanisms are still unclear, leading to unsatisfactory treatment outcomes.