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

Tai, Yi-Heng; Engels, Daniel; Locatelli, Giuseppe; Emmanouilidis, Ioanna; Fecher, Caroline; Theodorou, Delphine; Mueller, Stephan A.; Licht-Mayer, Simon; Kreutzfeldt, Mario; Wagner, Ingrid; de Mello, Natalia Prudente; Gkotzamani, Sofia-Natsouko; Trovo, Laura; Kendirli, Arek; Aljovic, Almir; Breckwoldt, Michael O.; Naumann, Ronald; Bareyre, Florence M.; Perocchi, Fabiana; Mahad, Don; Merkler, Doron; Lichtenthaler, Stefan F.; Kerschensteiner, Martin und Misgeld, Thomas (2023): Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions. In: Nature Metabolism, Bd. 5, Nr. 8: 1364-+

Abstract

In this study, Tai et al. provide insights into the metabolic and bioenergetic responses in the axonal compartment in the context of multiple sclerosis. Moreover, they show how upregulating the tricarboxylic acid cycle confers protection against neuroinflammation-induced energy deprivation. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198