Oligodendrogliopathy in Multiple Sclerosis: Low Glycolytic Metabolic Rate Promotes Oligodendrocyte Survival

Abstract

Multiple sclerosis (MS) lesions feature demyelination with limited remyelination. A distinct injury phenotype of MS lesions features dying back of oligodendrocyte (OL) terminal processes, a response that destabilizes myelin/axon interactions. This oligodendrogliopathy has been linked with local metabolic stress, similar to the penumbra of ischemic/hypoxic states. Here, we developed an in vitro oligodendrogliopathy model using human CNS-derived OLs and related this injury response to their distinct bioenergetic properties. We determined the energy utilization properties of adult human surgically derived OLs cultured under either optimal or metabolic stress conditions, deprivation of growth factors, and glucose and/or hypoxia using a Seahorse extracellular flux analyzer. Baseline studies were also performed on OL progenitor cells derived from the same tissue and postnatal rat-derived cells. Under basal conditions, adult human OLs were less metabolically active than their progenitors and both were less active than the rat cells. Human OLs and progenitors both used aerobic glycolysis for the majority of ATP production, a process that contributes to protein and lipid production necessary for myelin biosynthesis. Under stress conditions that induce significant process retraction with only marginal cell death, human OLs exhibited a significant reduction in overall energy utilization, particularly in glycolytic ATP production. The stress-induced reduction of glycolytic ATP production by the human OLs would exacerbate myelin process withdrawal while favoring cell survival, providing a potential basis for the oligodendrogliopathy observed in MS. The glycolytic pathway is a potential therapeutic target to promote myelin maintenance and enhance repair in MS.

Sublethal oligodendrocyte injury: A reversible condition in multiple sclerosis?

“…11 In the current study, we observed a significant decrease in OCR compared to our previous report, likely reflecting an even more sustained baseline injury to the cells. The initial time point of process withdrawal without cell death was associated with a significant decrease in overall cell respiratory activity, primarily driven by a decrease in glycolytic metabolism, as we previously described.…”

“…Our current data support the concept we proposed previously 11 that when challenged with a severe metabolic stress, OLs promote survival by sacrificing the "luxury function" 30 of macromolecular synthesis required to maintain and build myelin, instead switching to catabolic metabolism to promote cell survival. 11 Although autophagy is usually considered protective, excess is documented to be linked with cell death. 31 Makinodan et al, using OLs derived from embryonic day 16 rats, showed that process recovery could follow severing cell processes with a scalpel or inducing retraction by application of Nmethyl-D-aspartate agonist.…”

“…11 The cells were washed with XF assay medium containing 0.25g/l or 4.5g/l glucose (pH adjusted to 7.4) and equilibrated for 1 hour in the Seahorse incubator. Metabolic measurements were used as described previously.…”

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

“…Once fortified with additional glucose, oligodendrocytes release lactate, thereby maintaining energy supplies to myelinated axons in the optic nerve. Moreover, evidence from multiple sclerosis patient tissue suggests that oligodendrocytes in low glucose conditions decrease their lactate release (Rone et al, 2016), possibly imperiling myelin maintenance but allowing cell survival. This suggests that glia are responsive to axon activity through greater release of metabolic substrate, but they have limits.…”

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

“…Of interest, upon exposure to hypoxic stress, mature OLs in culture demonstrated significant reduction in their energy utilization, particularly in glycolitic ATP production. This was associated with cessation of myelin production, while favoring OLs survival (58). Thus, it is possible that nonlethal chronic hypoxemia or IH-stress negatively affect mitochondrial bioenergetic function in mature, differentiating OLs and their precursors which eventuates in poor axonal myelination in premature infants.…”