Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape

Abstract

Once believed to be part of the nervenkitt or "nerve glue" network in the central nervous system (CNS), oligodendroglial cells now have established roles in key neurological functions such as myelination, neuroprotection, and motor learning. More recently, oligodendroglia has become the subject of intense investigations aimed at understanding the contributions of its energetics to CNS physiology and pathology. In this review, we discuss the current understanding of oligodendroglial metabolism in regulating key stages of oligodendroglial development and health, its role in providing energy to neighboring cells such as neurons, as well as how alterations in oligodendroglial bioenergetics contribute to disease states. Importantly, we highlight how certain inputs can regulate oligodendroglial metabolism, including extrinsic and intrinsic mediators of cellular signaling, pharmacological compounds, and even dietary interventions. Lastly, we discuss emerging studies aimed at discovering the therapeutic potential of targeting components within oligodendroglial bioenergetic pathways.

Keywords: glycolysis; lactate; metabolism; myelin; oligodendrocyte; oligodendrocyte progenitor cell (OPC); remyelination.

Figure 1

Glucose metabolism in OPCs/OLs. Glucose is imported into the cell by GLUT transporters (GLUT1 is the most abundant GLUT transporter in OLs). Glucose is transformed into G-6-P by the rate-limiting enzyme hexokinase. G-6-P can enter the pentose phosphate pathway (PPP) or continue down the glycolytic pathway. In OPCs and OLs, there is significant PPP activity when compared to other cell types in the brain. The PPP pathway produces NADPH which is essential for cholesterol synthesis (for lipids) and for enhancing antioxidant activity. Furthermore, PPP generates ribose-5-phosphate (R-5-P) which is the backbone used in nucleotide synthesis and is critical in maintaining the proliferative function of cells like OPCs. R-5-P can be converted to F-6-P and enter back into the glycolytic pathway to generate a net of 2 ATP and 2 NADH molecules as well as pyruvate. Pyruvate is then converted to AcCoA by the PDH complex and enters the TCA cycle. The metabolites formed from the TCA cycle become electron donors of the electron transport chain, driving the hydrogen potential difference across the inner mitochondrial membrane to power ATP synthase and produce ATP. Created with BioRender.com.

Figure 2

Metabolic factors impacting oligodendroglial development and function. Oligodendrocytes (OLs) are metabolically active cells that both myelinate and provide trophic support to neurons, as well as supply metabolites to neurons and other cells of the CNS. Many metabolic factors can alter OL function including (but not limited to): glucose and lipid metabolism, reactive oxygen species (ROS) that can generate pro- or anti-OL effects, autophagy, cell signaling events, and diet. Abbreviations: PPP, pentose phosphate pathway; OXPHOS, oxidative phosphorylation; SOD, superoxide dismutase; mTORC1, mammalian target of Raptor complex I. Created with BioRender.com.