Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions

Abstract

IntroductionDemyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms.ResultsExpression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons.ConclusionIn conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0261-8) contains supplementary material, which is available to authorized users.

The Role of Mitochondria in Inflammation: From Cancer to Neurodegenerative Disorders

“…More complex is the scenario in MS, where cellular metabolism varies according to the activity of the disease. Specifically, in active MS demyelinating lesions, characterized by the presence of activated microglia and macrophages, increased levels of PDH complex, malate dehydrogenase (MDH) and KGDH were detected compared to normal white matter, indicating that glycolytic and TCA cycle pathways were increased [86]. On the contrary, in demyelinated axons, namely, inside the inactive lesion (plaque), KGDH activity was reduced, thus correlating with terminal axonal damage [86].…”

“…Specifically, in active MS demyelinating lesions, characterized by the presence of activated microglia and macrophages, increased levels of PDH complex, malate dehydrogenase (MDH) and KGDH were detected compared to normal white matter, indicating that glycolytic and TCA cycle pathways were increased [86]. On the contrary, in demyelinated axons, namely, inside the inactive lesion (plaque), KGDH activity was reduced, thus correlating with terminal axonal damage [86]. These findings suggest that the TCA cycle is definitely altered in NDDs, but upregulation or downregulation of its enzymes might change according to the type of disease and the type of cells involved.…”

Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects

“…In MS, the focus has been mainly on metabolic disturbances within the CNS, especially in neurons and axons, and mitochondrial injury as well as changes in glucose-metabolizing enzymes have been described in active MS lesions (57)(58)(59). In peripheral immune cells from RRMS patients, a pilot study suggested that immune cells from RRMS patients might exhibit altered activities in several complexes of the electron transport chain as well as key enzymes of glycolysis such as hexokinase I pointing towards an impaired mitochondrial respiration and concomitantly decreased glycolytic activity; however, the patient cohort investigated was rather small and active and stable patients were not separately investigated (16,60).…”

Involvement of the Warburg effect in non‐tumor diseases processes

“…The alteration of energy metabolism also is found in serum of MS patients (Tavazzi et al, ). Moreover, glycolytic shift may contribute to ongoing axonal degeneration in MS (Nijland et al, ).…”