Oligodendrogliopathy in Multiple Sclerosis: Relation to Low Glycolytic Metabolic Rate of Oligodendrocytes (I10.004)

Objective: To determine the relationship between the bio-energetic properties of oligodendocytes (OLs) and their response to metabolic stresses that mimic the multiple sclerosis (MS) lesion micro-environment. Background: The production of myelin by OLs is a highly energetic process, requiring mitochondrial oxidative phosphorylation (OXPHOS) for ATP production and glycolysis/lactate to provide the carbon backbones necessary for lipid biosynthesis. Oligodendrogliopathy, which features the dying back of oligodendrocyte terminal processes, is a distinct type of injury response observed in MS lesions. This dying back process in MS has been linked to metabolic stress, which in MS lesions reflect disturbed micro-circulation with associated ischemia and/or production of toxic metabolites that disturb mitochondrial energy metabolism (Lassmann 2003). Methods: We used OLs isolated from adult human brain specimens to examine their injury responses (survival, process extension) to reduced trophic factor, low glucose, and hypoxia conditions as a model of oligodendrogliopathy observed in MS lesions. We further examined the underlying bio-energetic properties of OLs using a Seahorse XF96 extracellular flux analyzer under the basal, metabolic stress and recovery conditions. Results: Human OLs grown under the above stress conditions for 48 hours showed only a marginal increase in [percnt] of TUNEL+ cells but a significant decrease in process area per cell. Basal aerobic glycolysis under optimal conditions provides the majority of ATP production in OLs. Under stress conditions, this ATP production is significantly decreased. Removal of stress conditions for 48 hours allowed for recovery of ATP production that occurred under the metabolic stress conditions. Conclusions: Oligodendrocytes under metabolic stress conditions show significant reduction in glycolytic ATP production that is required for myelin maintenance. Here we show that the restoration of optimal metabolic conditions can restore energy production in human OLs. It remains to be determined when such intervention will result in long-term cell survival. Disclosure: Dr. Cui has nothing to disclose. Dr. Rone has nothing to disclose. Dr. Khan has nothing to disclose. Dr. Bedard has nothing to disclose. Dr. Almazan has nothing to disclose. Dr. Ludwin has nothing to disclose. Dr. Kennedy has nothing to disclose. Dr. Antel has received compensation for activities with Novartis, Sanofi/Genzyme Inc., Biogen Idec, EMD Serono, Juno Therapeutics, and MedDay for serving on the advisory boards. Dr. Antel has received personal compensation in an editorial capacity for Mul