Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions

Abstract

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. We show that neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP deficiency, which precedes mitochondrial oxidation and calcium overload. This axonal energy deficiency is associated with impaired electron transport chain function, but also an upstream imbalance of tricarboxylic acid (TCA) cycle enzymes. Among these, isocitrate dehydrogenase 3 (Idh3), a rate-limiting enzyme of the TCA cycle, is depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of an Idh3 subunit ameliorates the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.