Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder of unclear etiology that affects many individuals worldwide. One of its hallmark symptoms is prolonged fatigue following exertion, a feature also observed in long COVID, suggesting an underlying dysfunction in energy production in both conditions. Here, mitochondrial dysfunction and its potential pathogenetic role in these disorders are reviewed.

Keywords: ER stress; ME/CFS; WASF3; long COVID; mitochondria.

Figure 1.. A model of how WASF3 may play a central role in regulating metabolism and immunity in response to ER stress and other signals

Upon ER stress, the level of WASF3 protein may rise at the contact sites between the endoplasmic reticulum (ER) and mitochondria. WASF3 disrupts the assembly of respiratory complexes, inhibiting mitochondrial respiration and oxidative phosphorylation. In parallel, WASF3 overexpression promotes actin polymerization, which drives glycolysis and further suppresses mitochondrial respiration. This metabolic shift may support immune system activation for host defense. However, prolonged activation of this pathway can lead to chronic inflammation and energy deficiency, contributing to the symptoms of ME/CFS. Created in BioRender. Hwang, P. (2024) https://BioRender.com/g19a699