Mitochondria — Does fatigue start in your cells?

Aim of the study: Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized.

Results: By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.

Aim of the study: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating neuroimmune disease, probably of post-viral multifactorial etiology. Unfortunately, no accurate diagnostic or laboratory tests have been established, nor are any universally effective approved drugs currently available for its treatment.

Results: A significant reduction in cognitive fatigue perception and overall FIS-40 score (p < 0.001 and p = 0.022, respectively) and an improvement in HRQoL (health-related quality of life (SF-36)) (p < 0.05) from baseline were observed within the experimental group over time. Statistically significant differences were also shown for sleep duration at 4 weeks and habitual sleep efficiency at 8 weeks in follow-up visits from baseline within the experimental group (p = 0.018 and p = 0.038, respectively). Overall, these findings support the use of CoQ10 plus NADH supplementation as a potentially safe therapeutic option for reducing perceived cognitive fatigue and improving the health-related quality of life in ME/CFS patients. Future interventions are needed to corroborate these clinical benefits and also explore the underlying pathomechanisms of CoQ10 and NADH administration in ME/CFS.

Aim of the study: Multiple Sclerosis (MS) is a chronic and progressive inflammatory disease of the central nervous system (CNS). Oxidative stress is a crucial mediator in multiple conditions, including the MS. Coenzyme Q10 (CoQ10) is a potent antioxidant, present in enzyme complexes of mitochondria, and involved in oxidative phosphorylation to produce adenosine triphosphate (ATP).

Results: The initial search yielded 237 articles, of which eight reports from six studies (total n = 195), including three RCTs, two semi-experimental studies, and one retrospective analysis were included. The effects of 2-3 months of CoQ10 supplementation on inflammatory factors, antioxidant enzyme system, and lipid peroxidation remain controversial in 200mg/day dose; however, 500mg/day of CoQ10 supplement can improve oxidative stress and inflammation, along with depression and fatigue amelioration in MS patients.

Aim of the study: Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage.

Results: Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS.

Aim of the study: Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role.

Results: CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations.

Aim of the study: Chronic fatigue syndrome (CFS) is a neurological disorder primarily characterized by persistent fatigue, post-exertional malaise, and cognitive dysfunction. Mitochondrial dysfunction is considered as a core mechanism underlying its pathological changes.

Results: This review summarized the research progress on acupuncture and moxibustion in regulating mitochondrial function for the treatment of CFS. The findings indicated that acupuncture and moxibustion can modulate mitochondrial quality control systems through multiple pathways, including repairing mitochondrial morphology and structure, promoting mitochondrial biogenesis, restoring mitochondrial dynamics balance, enhancing autophagy of damaged mitochondria, regulating calcium homeostasis, and modulating the activity of the electron transport chain (ETC) complexes, thereby improving mitochondrial function. In addition, acupuncture and moxibustion can further promote mitochondrial function recovery through reducing oxidative stress and inhibiting immune-inflammatory responses.