Author ORCID Identifier
https://orcid.org/0000-0003-3206-0617
Date of Award
Spring 5-5-2025
Document Type
Thesis (Ph.D.)
Department or Program
Biological Sciences
First Advisor
Dr. Robert A. Hill
Abstract
Oligodendrocytes are the myelinating cells of the central nervous system, known for modulating signal transmission, refining neural circuits, and providing metabolic support to axons. Oligodendrocytes are generated throughout life from oligodendrocyte precursor cells (OPCs) and are damaged or lost in demyelinating and neurodegenerative diseases and age-related pathologies. Thus, understanding the cellular checkpoints that occur during the generation and degeneration of oligodendrocytes is crucial for maintaining their population in health and recovering it in disease and aging.
Using high-resolution optical imaging, I have discovered a dynamic redistribution and subcellular partitioning of mitochondria during oligodendrogenesis. Mitochondria transiently expanded towards the differentiating OPC processes upon myelin formation, before drastically declining in the periphery and recovering in the soma upon myelin sheath compaction and oligodendrocyte maturation. This was accompanied by a transition in mitochondrial morphology, from elongated to short and punctate, and a shift in mitochondrial movement, from dynamically repositioning within the cell to becoming largely stationary. External factors, such as anesthesia and sedation, but not glutamatergic and GABAergic neuronal activity, modulated OPC mitochondrial motility.
Next, using a DNA damage model to induce death in the oligodendrocyte lineage, I discovered that dying mature oligodendrocytes largely lose their mitochondria early after the damage, but persist for several weeks in their absence. In contrast, the other cells in the lineage die and get cleared up within hours to days. In addition, I determined that mitochondrial fission protein 1 (FIS1) levels are high in mature oligodendrocytes and may play a role in maintaining their health, as conditionally knocking out Fis1 in the oligodendrocyte lineage led to increased DNA double-strand breaks in oligodendrocytes. Lastly, aging was associated with mitochondrial changes in oligodendrocytes and their precursors, potentially contributing to oligodendrocyte degeneration and inefficient regeneration.
Overall, this work determines mitochondrial alterations linked to oligodendrocyte generation, degeneration, and aging for the first time in the intact brain. In addition, it discovers new spatiotemporal windows and suggests molecular targets that could influence how oligodendrocyte lineage cells behave in both physiological and pathological conditions.
Recommended Citation
Bame, Xhoela, "Mitochondrial Network Expansion and Loss During Oligodendrocyte Life and Death" (2025). Dartmouth College Ph.D Dissertations. 341.
https://digitalcommons.dartmouth.edu/dissertations/341
