Fatigue is often described by patients as a lack of energy, mental or physical tiredness, diminished endurance, and prolonged recovery after physical activity. Etiologic mechanisms underlying fatigue are not well understood; however, fatigue is a hallmark symptom of mitochondrial disease, making mitochondrial dysfunction a putative biological mechanism for fatigue. Therefore, this review examined studies that investigated the association of markers of mitochondrial dysfunction with fatigue and proposes possible research directions to enhance understanding of the role of mitochondrial dysfunction in fatigue. A thorough search using PubMed, Scopus, Web of Science, and Embase databases returned 1220 articles. After the application of inclusion and exclusion criteria, a total of 25 articles meeting eligibility criteria were selected for full review. Dysfunctions in the mitochondrial structure, mitochondrial function (mitochondrial enzymes and oxidative/nitrosative stress), mitochondrial energy metabolism (ATP production and fatty acid metabolism), immune response, and genetics were investigated as potential contributors to fatigue. Carnitine was the most investigated mitochondrial function marker. Dysfunctional levels were reported in all the studies investigating carnitine; however, the specific type of carnitine that was dysfunctional varied. Genetic profiles were the second most studied mitochondrial parameter. Six common pathways were proposed: metabolism, energy production, protein transport, mitochondrial morphology, central nervous system dysfunction and post-viral infection. Coenzyme Q10 was the most commonly investigated mitochondrial enzyme. Low levels of Coenzyme Q10 were consistently associated with fatigue. Potential targets for further investigation were identified as well as gaps in the current literature.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

Fatigue is a prevalent and potentially debilitating symptom that impacts the health-related quality-of-life of individuals diagnosed with acute and chronic medical conditions. Yet, its etiologic mechanism is not fully understood. Additionally, the assessment and determination of the clinical meaning of fatigue and its multidimensionality may vary by medical condition. A scoping literature review was conducted to investigate how fatigue is defined and measured, including its dimensions, in non-oncologic medical conditions. The PubMed database was searched using keywords. Overall, 8376 articles were screened at the title/abstract levels, where 293 articles were chosen for full-text review that mentioned fatigue or included fatigue measures. The review of the full text excluded 246 articles that did not assess at least one fatigue dimension using validated questionnaires and clinical tests. The final set included 47 articles. Physical fatigue was the most assessed fatigue dimension and the Multidimensional Fatigue Inventory was the most widely used questionnaire to assess fatigue in this review. This review was limited by including only English-language publications and using PubMed as the sole database for the search. This review affirms that fatigue is a multidimensional construct, agnostic of medical condition, and that individual fatigue dimensions can be measured by validated clinical measures. Future research should focus on expanding the repertoire of clinical measures to assess specific fatigue dimensions.

Fatigue is a disabling, multifaceted symptom that is highly prevalent and stubbornly persistent. Although fatigue is a frequent complaint among patients with fibromyalgia, it has not received the same attention as pain. Reasons for this include lack of standardized nomenclature to communicate about fatigue, lack of evidence-based guidelines for fatigue assessment, and a deficiency in effective treatment strategies. Fatigue does not occur in isolation; rather, it is present concurrently in varying severity with other fibromyalgia symptoms such as chronic widespread pain, unrefreshing sleep, anxiety, depression, cognitive difficulties, and so on. Survey-based and preliminary mechanistic studies indicate that multiple symptoms feed into fatigue and it may be associated with a variety of physiological mechanisms. Therefore, fatigue assessment in clinical and research settings must consider this multi-dimensionality. While no clinical trial to date has specifically targeted fatigue, randomized controlled trials, systematic reviews, and meta-analyses indicate that treatment modalities studied in the context of other fibromyalgia symptoms could also improve fatigue. The Outcome Measures in Rheumatology (OMERACT) Fibromyalgia Working Group and the Patient Reported Outcomes Measurement Information System (PROMIS) have been instrumental in propelling the study of fatigue in fibromyalgia to the forefront. The ongoing efforts by PROMIS to develop a brief fibromyalgia-specific fatigue measure for use in clinical and research settings will help define fatigue, allow for better assessment, and advance our understanding of fatigue.