Rone MB, Cui QL, Fang J, Wang LC, Zhang J, Khan D, Bedard M, Almazan G, Ludwin SK, Jones R, Kennedy TE, Antel JP. Oligodendrogliopathy in Multiple Sclerosis: Low Glycolytic Metabolic Rate Promotes Oligodendrocyte Survival. J Neurosci. 2016;36(17):4698-707.
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.
Baseline studies were also performed on OL progenitor cells derived from the same tissue and post-natal 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.
SIGNIFICANCE STATEMENT: The neurologic deficits that characterize multiple sclerosis (MS) reflect disruption of myelin (demyelination) within the CNS and failure of repair (remyelination). We define distinct energy utilization properties of human adult brain-derived oligodendrocytes and oligodendrocyte progenitor cells under conditions of metabolic stress that model the initial relapsing and subsequent progressive phases of MS. The observed changes in energy utilization affect both cell survival and myelination capacity. These processes may be amenable to therapeutic interventions to limit the extent of cumulative tissue injury and to promote repair in MS.
Glycolysis is a determined sequence of ten enzyme
-catalyzed reactions. The intermediates provide entry points to glycolysis. For example, most monosaccharides, such as fructose
, can be converted to one of these intermediates. The intermediates may also be directly useful. For example, the intermediate dihydroxyacetone phosphate
(DHAP) is a source of the glycerol that combines with fatty acids to form fat.
Glycolysis is an oxygen independent metabolic pathway, meaning that it does not use molecular oxygen (i.e. atmospheric oxygen) for any of its reactions.
However the products of glycolysis (pyruvate
) are sometimes disposed of
using atmospheric oxygen. When molecular oxygen is used in the disposal of the products of glycolysis the process is usually referred to as aerobic
, whereas if the disposal uses no oxygen the process is said to be anaerobic
The entire glycolysis pathway can be separated into two phases:
- The Preparatory Phase – in which ATP is consumed and is hence also known as the investment phase
- The Pay Off Phase – in which ATP is produced.