N-Acetylglucosamine Selectively Attenuates Neuroinflammation in a Mouse Model of Mitochondrial Dysfunction.

AIM: Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characterize the progression of neurodegeneration in a mouse model of fatal mitochondrial encephalopathy and to evaluate the therapeutic potential of oral N-acetylglucosamine supplementation. METHODS: A mouse model of primary coenzyme Q deficiency was used to examine neurodegeneration at presymptomatic, symptomatic and terminal stages. Neuronal integrity, glial activation, myelination and inflammatory responses were assessed using histological, molecular and ultrastructural approaches, together with behavioral analysis of motor coordination. N acetylglucosamine was administered orally from 1 month of age, and its effects on neuroinflammation, myelin integrity and motor performance were evaluated. RESULTS: Astrocyte activation and neuronal loss were detected before the onset of clinical symptoms, whereas proinflammatory microglia appeared at later disease stages. Early myelin abnormalities were accompanied by an initial increase in oligodendrocyte precursor cells, suggesting a compensatory response to early myelin stress. Oral N-acetylglucosamine supplementation reduced glial activation and neuroinflammatory markers, likely through modulation of inflammatory signaling pathways. Although treatment did not fully reverse structural damage or restore myelin protein expression, it led to a significant improvement in motor coordination. CONCLUSION: These findings define a temporal sequence of early glial activation, neuronal loss, and myelin alterations in mitochondrial encephalopathy. Targeting glial responses and neuroinflammation at early disease stages may mitigate neurodegenerative progression and improve functional outcomes, highlighting a physiologically relevant therapeutic window for mitochondrial disorders.