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

Yi-Heng Tai, Daniel Engels, Giuseppe Locatelli, Ioanna Emmanouilidis, Caroline Fecher, Delphine Theodorou, Stephan A Müller, Simon Licht-Mayer, Mario Kreutzfeldt, Ingrid Wagner, Natalia Prudente de Mello, Sofia-Natsouko Gkotzamani, Laura Trovò, Arek Kendirli, Almir Aljović, Michael O Breckwoldt, Ronald Naumann, Florence M Bareyre, Fabiana Perocchi, Don MahadDoron Merkler, Stefan F Lichtenthaler, Martin Kerschensteiner, Thomas Misgeld

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Inflammation in the central nervous system 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, with several, including key rate-limiting, enzymes being depleted in neuronal mitochondria in experimental models and in MS lesions. Notably, viral overexpression of individual TCA enzymes can ameliorate the axonal energy deficits in neuroinflammatory lesions, suggesting that TCA cycle dysfunction in MS may be amendable to therapy.

Original languageEnglish
JournalNature Metabolism
Early online date10 Jul 2023
Publication statusE-pub ahead of print - 10 Jul 2023


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