Redefining Mitochondrial Therapy for ME/CFS: The Case for MOTS-c

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multi-system disease characterized by profound fatigue, post-exertional malaise (PEM), and a constellation of immune, neurological, and autonomic symptoms. Despite its global prevalence, the pathophysiology of ME/CFS remains elusive, and there are no FDA-approved treatments targeting the underlying mechanisms. Symptom-based pharmacologic management is often complicated by hypersensitivity reactions and mitochondrial toxicity. Non-pharmacologic interventions, such as energy conservation, autonomic regulation, and nutritional strategies, are frequently employed to mitigate symptom burden. Emerging research points to mitochondrial dysfunction as a core contributor to ME/CFS pathology, marked by impaired ATP production, oxidative stress, and bioenergetic failure. Mitochondrial-derived peptides (MDPs), particularly MOTS-c, offer a novel therapeutic avenue by enhancing mitochondrial biogenesis, reducing oxidative damage, and modulating inflammatory responses through AMPK and NRF2 activation. Preclinical evidence suggests that MOTS-c improves glucose metabolism, increases mitochondrial density, and enhances fatigue resistance. However, safety and efficacy data in humans are lacking. Future investigations are needed to evaluate MOTS-c's potential as a disease-modifying therapy in ME/CFS.