Mitoproteomics of neuronal mitochondria of EAE mice

Inflammation in the central nervous system (CNS) can impair the function of neuronal mitochondria and contributes to axon degeneration in the common neuroinflammatory disease multiple sclerosis (MS). Here we combine cell type-specific mitochondrial proteomics with in vivo biosensor imaging to dissect how inflammation alters the molecular composition and functional capacity of neuronal mitochondria. Neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP depletion, which precedes mitochondrial oxidation and calcium overload. This early axonal energy crisis is associated with impaired electron transport chain function, but also an upstream dysbalance of tricarboxylic acid (TCA) cycle enzymes. Isocitrate dehydrogenase 3 (Idh3), the rate limiting enzyme of the TCA cycle, is depleted in neuronal mitochondria in experimental models and in human MS lesions. Notably, viral overexpression of Idh3 can rectify the axonal energy deficits, suggesting that TCA cycle dysfunction in neuroinflammation may be amendable to therapy.