Association of mitochondrial dysfunction and fatigue: A review of the literature

Abstract

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 1,220 articles. After 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.

Membrane Lipid Replacement: Clinical Studies Using a Natural Medicine Approach to Restoring Membrane Function and Improving Health

“…Fatigue is the most common complaint of patients seeking general medical care [21] [22], and it is associated with most if not all chronic medical conditions as well as natural aging [21]. Fatigue is considered a complex, multidimensional sensation that is not well understood but is perceived to be a loss of overall energy, mental or physical tiredness, a feeling of exhaustion or diminished endurance, and an inability to perform even simple tasks without exertion [21]- [23]. At the cellular level moderate to severe fatigue has been related to loss of mitochondrial function and diminished production or leakage of ATP from mitochondria [20] [23] [24].…”

“…In fact, fatigue in general, and fatiguing illnesses in particular, are characterized by losses in mitochondrial function [20] [23] have reviewed the literature on fatigue and the association of mitochondrial dysfunction and its possible causes. In addition, they examined the association of the levels of various mitochondrial metabolites, such as acylcarnitine and coenzyme Q10, with fatigue in selected publications [23].…”

“…Various mental disorders, such as schizophrenia, bipolar disease, and others, may be associated with mitochondrial dysfunction, but the links are less clear [23]. These patients are also often characterized with moderate to severe depression.…”

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

“…Compared with many other chronic diseases, patients with ME/CFS have a lower quality of life, with major implications for patients and their families and for society (2,3). Recent research suggests that ME/CFS is associated with changes in fundamental processes of energy metabolism (4,5). Importantly, such metabolic changes may arise from dysregulated physiological response mechanisms that may be relevant in ME/CFS, such as immune activation, inflammation, and receptor-mediated signaling (6,7).…”

Understanding cancer-related fatigue: advancing the science

“…Proposed etiologic mechanisms of CRF implicate immune system dysregulation, impaired nerve conduction, neuroendocrine and neurotransmitter dysregulation, and energy depletion [5–7]. Central mechanisms proposed include disruptions in basal ganglia and frontal lobe function, hypothalamic–pituitary–adrenal axis dysfunction, and enhanced proinflammatory cytokine release affecting neuronal metabolism [8–11].…”