Assessment of Mitochondrial Dysfunction in Experimental Autoimmune Encephalomyelitis (EAE) Models of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I–IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.

Coenzyme Q10 and the exclusive club of diseases that show a limited response to treatment

“…These findings accompanied depolarization of the axonal mitochondria and axons themselves, thus, correlating with neurological deficits. Evidence of mitochondrial dysfunction is relatively unexplored in other tissues; however, Hargreaves et al [41] reported statistically significant alterations to ETC complex I and complex II/III (succinate: ubiquinone reductase) activities at the pre-symptomatic and asymptomatic stages in spinal cord, jaw muscle and liver tissues of EAE mouse models of MS. ETC complex I has been reported to be the main site of ROS production in the ETC [42]; thus, increased levels of oxidative stress reported in MS patients [43] may be attributable to a decrease observed in complex I activity [39,40].…”

Metabolic determinants of leukocyte pathogenicity in neurological diseases

“…Nonetheless, future works are needed to differentiate if alterations in glycolysis and respiration occur in leukocytes prior to their trafficking in the CNS, or if they become highly glycolytic upon infiltration into the CNS parenchyma. One recent work has addressed this question in murine EAE, where the authors found that changes in enzymatic activity of mitochondrial respiratory chain complexes occurred prior to symptom onset, and these metabolic alterations were observed not only in the CNS but also in the periphery (Ng, Sadeghian, Heales, & Hargreaves, 2019). Even so, timing of metabolic changes in specific leukocyte types during MS has not yet been measured.…”

Impact of Exercise on Immunometabolism in Multiple Sclerosis

“…This facilitates trans-endothelial migration of monocytes into the brain’s parenchyma, where they differentiate into proinflammatory macrophages [ 110 ]. Similarly, loss of mitochondrial respiratory function by ROS/RNS-induced oxidative damage to membrane phospholipids and mitochondrial DNA can result in reduced ATP production that, if left uncompensated, leads to a loss of tissue function and, consequently, clinical symptoms such as muscle fatigue in MS and EAE [ 111 , 112 ].…”