The textual definition of pain describes it as the physical suffering caused by an illness injury. Nevertheless, pain can also be inflicted or felt if a social or emotional burden enables this discomfort. Pain is physically felt by a mechanism called nociception which results from the activation of sensory neurons; this mechanism has a protective effect as it detects pain and stops whatever we are doing to get this sensation. On the other hand, a lesion or injury of this sensory system can lead to dysfunction and promote neuropathic pain. Furthermore, oxidative stress, a joint promoter of disease, also drives mitochondrial dysfunction, which is present in muscles that exhibit localized pain and fibromyalgia patients.
This disorder mainly affects the musculoskeletal system and is typically characterized by chronic widespread pain and hyperalgesia. Furthermore, in search of fibromyalgia (FM) etiology, imaging techniques have found that FM does not have a peripheral origin. It is more likely to have an altered nociceptive/pain morphology. On the other hand, recent studies report there are central nervous system alterations and muscular dysfunctions.
The fundamental role of mitochondrial function associates with the detrimental effect of oxidative stress. Furthermore, mitochondrial function is dependent on its structure, and novel studies have reported a loss of mitofusin2 (Mfn2) in FM patients. Indeed, the failure of Mfn2, an outer mitochondrial membrane protein, results in a reduced rate of mitochondrial fusion, meaning that small mitochondrial can no longer form more prominent and more functional organelles. In addition, Mfn2 has a crucial role in maintaining the terpenoids biosynthesis pathway, ultimately promoting coenzyme Q10. An alteration in these molecules’ function, maintenance, and synthesis reflects an altered electron transfer chain function, ultimately affecting energy production and increasing oxidative stress.
Another novel finding is the modulation of Mfn2 by the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) signaling pathway. Indeed, PGC-1alpha is a transcription coactivator playing a crucial role in cellular metabolism, mitochondrial biogenesis, and muscle tissue remodeling. Also, this transcription coactivator is an essential factor in the regulation of carbohydrates and lipids.
In the context of mitochondrial dysfunction and fibromyalgia, we can state the following associations:
A study with the objective to determine how muscle metabolism affected pain sensation was performed in 33 FM patients and compared with 31 controls. The main results were as following:
This study found elevated pyruvate levels in the muscles of FM patients: Pyruvate is the end product of the glycolysis metabolic pathway in the cell cytoplasm. Once produced, the mitochondrial pyruvate carrier is responsible for transporting it into the mitochondria to be converted into Acetyl-CoA, enter the Tricarboxylic acid cycle, and ultimately go through the electron transport chain, and produce ATP. Nevertheless, if this mechanism cannot happen, pyruvate can easily transform into lactate in the cytosol via lactate dehydrogenase. Lactate can be transported to the muscle mitochondria and metabolized to produce ATP.
This study and many others found consistent mitochondrial alterations observed by increased pyruvate levels, lower concentrations of ATP and phosphocreatine. These alterations coincide with elevated oxidative stress, altered mitochondrial fusion and fission, apoptosis regulation, and mitochondrial structural integrity.
Furthermore, as all of these mechanisms rely on PGC-1α modulation, it is clear that the treatment for FM needs to change gears and focus on mitochondrial function and integrity.
The connection between pain and mitochondrial function is related to this organelle’s integrity and the potential to produce energy from a substrate. Nevertheless, if we focus on treating the problem from the route, the best way to improve mitochondrial function and reduce the pain sensation would be to stimulate PGC-1alpha function. In addition, increasing antioxidants and vitamins (cofactors of the enzymes used in glycolysis, TCA, ETC) and promoting Coenzyme Q10 increases energy production and counteracts oxidative stress excess.- Ana Paola Rodríguez Arciniega, MS
St John Smith, Ewan. “Advances in understanding nociception and neuropathic pain.” Journal of neurology vol. 265,2 (2018): 231-238. doi:10.1007/s00415-017-8641-6
Favero, Gaia et al. “Mitochondrial Dysfunction in Skeletal Muscle of a Fibromyalgia Model: The Potential Benefits of Melatonin.” International journal of molecular sciences vol. 20,3 765. 11 Feb. 2019, doi:10.3390/ijms20030765
Bost, Frederic, and Lisa Kaminski. “The metabolic modulator PGC-1α in cancer.” American journal of cancer research vol. 9,2 198-211. 1 Feb. 2019
Gerdle, Björn et al. “Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance.” Journal of clinical medicine vol. 9,11 3527. 31 Oct. 2020, doi:10.3390/jcm9113527
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