Histopathological comparison of Kearns-Sayre syndrome and PGC-1α-deficient mice suggests a novel concept for vacuole formation in mitochondrial encephalopathy.

Despite the current hypotheses about myelinic and astrocytic ion-dyshomeostasis underlying white (WM) and grey matter (GM) vacuolation in mitochondrial encephalopathies, there is a paucity of data on the exact mechanism of vacuole formation. To revisit the concepts of vacuole formation associated with mitochondrial dysfunction, we performed a comparative neuropathological analysis in Kearns-Sayre syndrome (KSS) and full-length peroxisome proliferator-activated receptor-g coactivator-1a (FL-PGC-1a)-deficient mice, a recently proposed morphological model of mitochondrial encephalopathies. Brain tissues from an individual with genetically proven KSS (22-year-old man) and aged FL-PGC-1a-deficient and wild-type (male, 70-75-week-old) mice were analysed using ultrastructural and immunohistochemical methods, with a specific focus on myelin-related, oligodendroglial, axonal and astrocytic pathologies. Besides demonstrating remarkable similarities in the lesion profile of KSS and FL-PGC-1a-deficient mice, this study first provides morphological evidence for the identical origin of WM and GM vacuolation as well as for the presence of intracytoplasmic oligodendroglial vacuoles in mitochondriopathies. Based on these observations, the paper proposes a theoretical model for the development of focal myelin vacuolation as opposed to the original concepts of intramyelin oedema. Placing oligodendrocytes in the centre of tissue lesioning in conditions related to defects in mitochondria, our observations support the rationale for cytoprotective targeting of oligodendrocytes in mitochondrial encephalopathies, and may also have implications in brain aging and multiple sclerosis, as discussed.