Mitochondrial dynamics underlying oligodendrocyte generation - PROJECT SUMMARY Myelin has evolved to speed up, finely tune, and increase the metabolic efficiency of electrical signal transmission in the brain. In numerous human diseases, myelin degenerates, ultimately resulting in devastating motor and cognitive impairment. One key reason that this degeneration progresses to functional impairments is the decline in the ability of resident oligodendrocyte precursor cells (OPCs) to generate new myelinating oligodendrocytes and replace the dying cells. To generate new oligodendrocytes, OPCs go through many cellular and molecular checkpoints, coordinating external microenvironmental signals with internal genetic, epigenetic, and metabolic states. Given this complexity, there are still many questions related to how these signals are integrated within the cell to ultimately result in the cell fate decision to transform into a postmitotic myelinating oligodendrocyte or remain a proliferative OPC. Mitochondrial activity has been shown to play important roles in similar fate decisions in other cell types throughout the body in addition to playing major roles in cell death pathways, however, less is known about how these organelles impact OPC fate, oligodendrocyte generation, and oligodendrocyte death in the intact brain. To directly study this, we have developed advanced techniques for high resolution imaging and manipulation of mitochondria throughout the oligodendrocyte lineage. These techniques permit longitudinal analyses of mitochondrial structure, localization, and dynamics in real time all in the live mammalian cerebral cortex. Here we propose to use these approaches to determine how disruptions and alterations in mitochondrial dynamics, characterized by mitochondrial fission, fusion, motility, generation, and degradation, impact OPC fate and oligodendrocyte survival. These experiments will be performed in the context of development, adulthood, aging, and in demyelination models, thus revealing the precise role mitochondria play in oligodendrocyte generation, plasticity, death, and regeneration. Ultimately, these studies will reveal multiple aspects of cell metabolism with a mitochondrial lens providing a critical foundation to understand this multifunctional organelle in oligodendrocyte physiology and pathology.
