Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a condition characterized by recurrent and constant fatigue that does not improve with rest. Symptoms of ME/CFS include dizziness, exhaustion, problems with concentrating, and sleeping. Researchers have not yet been able to pinpoint the cause of ME/CFS nor is there any approved treatment. Recent research literature suggests predisposing genetic factors, epigenetic modifications, and presence of immunologic disorder are involved. In addition, the impairment of the mitochondrial energy-generating metabolic processes presents unexplained fatigue, the hallmark feature of the illness. ME/CFS patients have been reported to show reduced ability to utilize glucose as energy via OXPHOS, all the while their mitochondria preferentially use alternate sources of energy. However, the severely affected ME/CFS experience mitochondrial and glycolytic impairments compared to only mitochondrial impairment in moderately affected. Thus, scientific interest has increased in identifying the candidate therapies to relieve the ME/CFS associated clinical manifestations.
Objective: Mitochondrial-derived peptides (MDPs), specifically mitochondrial ORF of the twelve S-c (MOTS-c), a metabolic homeostasis regulator is being evaluated as a potential therapy for the mitochondrial and glycolytic impairments associated Fatigue in ME/CFS.
Method: The data collected will be based upon results from various literature reviews.
Results: MOTS-c is a peptide expressed by a mitochondrial gene that regulates the energy production of the mitochondria. MOTS-c regulates nuclear genes, including those related to metabolism, and glucose and amino acid metabolism in skeletal muscle. It also mediates an exercise-induced mitohormesis response stimulating physiological adaptation and increased tolerance to exercise. MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, and inflammatory response. Protein levels of mitochondrial biogenesis are reported to increase in mammalian cells when treated with Mots-C. The endocrine and exercise mimetic effect of Mots-C is displayed as raised NAD+ levels and insulin resistance in rodent models. In addition, MOTS-c treatment activates peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, which is a modulator of mitochondrial physiology and glucose uptake (via GLUT4). Moreover, Mots-C is known to increase the protein expression of TFAM, COX4, and NR, all mitochondrial biogenesis fusion proteins. Interestingly, ME/CFS patients have reduced Mots-C expression, showed irregular mitochondrial fusion, and presented symptoms whose biochemistry overlaps with targets of activity of Mots-C. Considering the important physiological spectrum of MOTS-c activity, it appears as a viable candidate for ME/CFS associated Fatigue.
Conclusion: The results of this study demonstrate that the peptide MOTS-c plays an essential physiological role in the mitochondrial function and appears to be a promising therapy for ME/CFS.
