Dying oligodendrocytes persist without mitochondria

Myelin is an insulating, multi-layered membrane that supports axonal integrity and neural communication. Different stressors impair myelinating oligodendrocytes, leading to demyelination, inflammation, and neurodegeneration. The intracellular processes underlying oligodendrocyte degeneration and death are unclear. Here, using optically targeted DNA damage that causes single-cell demyelination, we reveal that injured mature oligodendrocytes lose mitochondria within days and persist without them for weeks to months before cell death. This differs from other oligodendrocyte lineage cells, which exhibit acute mitochondrial changes followed by rapid cell death. Conditional deletion of the mitochondrial-related gene, <i>Fis1,</i> in mature oligodendrocytes, similarly causes acute loss of mitochondria and prolonged cell death. The unique cell death is characterized by nuclear changes, intracellular stress, and markers of disease-associated oligodendrocytes. Thus, mitochondrial loss may be an early marker of oligodendrocyte pathology, and mitochondrial quality control is required for oligodendrocyte and myelin homeostasis.