Changes in mitochondrial function in patients with neuromyelitis optica; correlations with motor and cognitive disabilities

Abstract

Background Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease that mainly affects optic nerves and spinal cord. Besides, loss of motor and cognitive function has been reported as important symptoms of disease. Objective Here we investigated the mitochondrial dysfunction and metabolic alterations in NMO patients and evaluate their correlation with disease progress, disability and cognitive impairment. Methods The individuals (12 controls and 12 NMO) were assessed for disease severity by expanded disease status scale (EDSS), cognitive function via symbol digit modalities test (SDMT) and fine motor disability by 9-hole peg test (9-HPT). We have measured Sirtuin 1 (SIRT1), SIRT3, mitochondrial complex I, complex IV, aconitase and α-ketoglutarate dehydrogenase (α-KGD) activity in peripheral blood mononuclear cells (PBMCs). Furthermore, SIRT1, pyruvate, lactate and cytochrome c (Cyt c) were determined in plasma. Results Our results exhibited increased 9-HPT time in NMO patients. 9-HPT results correlated with EDSS; and SDMT negatively correlated with disease duration and number of attacks in patients. Investigation of PBMCs of NMO patients exhibited a decrease of mitochondrial complex I and IV activity that was significant for complex IV. Besides, complex I activity was negatively correlated with 9-HPT time in NMO group. In the plasma samples, a correlation between pyruvate to lactate ratio and EDSS in NMO patients was found and a negative correlation between Cyt c concentration and SDMT was detected.

Mitochondria–A target for attenuation of astrocyte pathology

“…Mitochondrial dysfunction has been implicated in motor and cognitive symptoms of NMOSD (Foolad et al, 2020), and CSF correlates were associated to development of pathology (Yamashita et al, 2018;Peng et al, 2020). Unexpectedly, we observed here that changes in mitochondrial function caused by etomoxir resulted in amelioration of astrocyte pathology.…”

“…The pathological hallmarks of neuromyelitis optica spectrum disorder (NMOSD) include astrocyte pathology, caused by disease-specific autoantibody against the astrocyte water channel aquaporin-4 (AQP4) in the central nervous system (CNS) (Bennett and Owens, 2017;Weinshenker and Wingerchuk, 2017). Recently mitochondrial dysfunction has been suggested to play a role in disease progression, disability level and cognitive impairment (Foolad et al, 2020). Mitochondrial DNA in cerebrospinal fluid was elevated in the acute phase of NMOSD (Yamashita et al, 2018) and associated to disease severity (Peng et al, 2020).…”

Anti-AQP4–IgG-positive Leigh syndrome: A case report and review of the literature

“…The AQP4 protein is abundantly expressed in the foot processes of astrocytes that are adjacent to the blood vessels and piamater (around the blood–brain barrier) ( 23 ), which is a common site of involvement in LS. A recent study found that mitochondrial dysfunction in the CNS and the peripheral blood may contribute to disease progression and the disability level in patients with NMOSD ( 24 ). In patients with LS, mitochondrial dysfunction leads to cell edema and hypoxia, which results in the loss of energy-dependent solute homeostasis and drives water influx down an osmotic gradient into perivascular astrocytes, which ultimately causes swelling ( 25 ).…”

Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system

“…OXPHOS is a critical metabolic pathway for the differentiation and immunosuppressive function of Tregs ( 15 – 17 ). Therefore, decreased activity and expression of respiratory chain complexes in autoimmune diseases of the CNS, such as MS and NMOSD, can contribute to the abnormal number and function of Tregs ( 32 , 33 , 77 , 80 , 81 ). Weinberg et al.…”

“…Recent studies have found abnormal mitochondrial morphology, impaired cristae organization, reduced activity and expression of respiratory chain complexes, decreased expression of cytochrome C, increased content of mitochondrial DNA (mtDNA) and mitochondrial reactive oxygen species (mtROS), and damaged mitophagy in Tregs of patients with autoimmune diseases of the CNS such as MS and NMOSD (31)(32)(33). Therefore, mitochondrialregulated Tregs may be involved in the occurrence and progression of autoimmune diseases of the CNS (31).…”