In recent years, evidence of white matter involvement in patients with mitochondrial disorders has been increasing. Given the high-energy demand nature of the brain, this tissue is preferentially affected by energy deficiency caused by mitochondrial dysfunctions. After birth, partial oxygen pressures rise in the central nervous system (CNS) and induce profound metabolic changes. These changes precede the onset of myelination, a process in which oligodendrocyte precursor cells (OPCs) differentiate and engage with axons to invest them with complex multilamellar sheaths. Myelin sheaths enable rapid saltatory signal propagation, synchronised signal conduction, and provide metabolic support to axons. Loss of myelin integrity leads to axonal degeneration and is a hallmark of many neurological conditions. The complex morphological and functional changes occurring during myelination are likely associated with significant energy demands. In particular, the present series of in vitro and vivo experiments studied the role of glucose energy metabolism in the context of OPC differentiation and myelination. The results in this thesis demonstrate 1) profound metabolic remodelling from a low to a high energy state during OPC differentiation and myelination. Both processes are 2) particularly dependent on oxidative phosphorylation, 3) and independent from lactate production. 4) The differentiation of OPCs entails expansion and transport of mitochondria into the cell processes, 5) mediated by a combination of de novo biogenesis and fission and fusion. 6) Both differentiation and myelin sheath formation are highly dependent on ATP. 7) Enhancing mitochondrial metabolism is able to promote OPC differentiation.

Investigating how mitochondria control OPC differentiation uncovered the role of reactive oxygen species (ROS) as an important and novel signalling mechanism, with potential therapeutic application. It was found that 8) modulating ROS feedbacks back to the mitochondria, upregulating biogenesis. Most importantly, inducing mitochondrial activity increases the number and the length of myelin sheaths formed by individual oligodendrocytes, whilst decreasing mitochondrial biogenesis reduces the length and number of internodes of individual cells. Therefore, 9) ROS determines how many myelin sheaths are formed by a single oligodendrocytes and how long individual myelin sheaths are, 10) in a PI3K-Akt-FoxO3a-Tfam pathway dependent way. These results provide answers to fundamental questions of oligodendrocyte biology and may have important implications for the development of future treatments. Moreover, this is the first study that demonstrates a regulatory role of mitochondrial activity with regards to the number and length of myelin sheaths formed by individual oligodendrocytes.