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Tai, Y.H.* ; Engels, D.* ; Locatelli, G.* ; Emmanouilidis, I.* ; Fecher, C.* ; Theodorou, D.* ; Müller, S.A.* ; Licht-Mayer, S.* ; Kreutzfeldt, M.* ; Wagner, I.* ; Prudente de Mello, N. ; Gkotzamani, S.N.* ; Trovò, L.* ; Kendirli, A.* ; Aljović, A.* ; Breckwoldt, M.O.* ; Naumann, R.* ; Bareyre, F.M.* ; Perocchi, F. ; Mahad, D.* ; Merkler, D.* ; Lichtenthaler, S.F.* ; Kerschensteiner, M.* ; Misgeld, T.*

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

Nat. Metab. 5, 1364-1381 (2023)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Progressive Multiple-sclerosis; High-dose Biotin; Isocitrate Dehydrogenase; Neurodegeneration; Mitochondria; Mechanisms; Cancer; Dysfunction; Metabolism; Neurons

ISSN (print) / ISBN 2522-5812

e-ISSN 2522-5812

Journal Nature metabolism

Quellenangaben Volume: 5, Issue: 8, Pages: 1364-1381

Publisher Springer

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)

Grants European Research Council (ERC) under the European Union
German Federal Ministry of Research and Education (Competence Network Multiple Sclerosis)
Verein Therapieforschung fuer MS-Kranke e.V.'
ERC under the European Union
Pioneer Grant from Doppelganger Biosystem GmbH
German Center for Neurodegenerative Diseases
Munich Center for Systems Neurology
Deutsche Forschungsgemeinschaft (DFG)
Doppelganger Biosystem GmbH for metabolic modeling
Swiss National Science Foundation
Gertrud Reemtsma Foundation
Emmy Noether Program of the DFG
EMBO Fellowships
Swiss National Science Foundation fellowship
TUM Graduate School via the PhD Program Medical Life Sciences and Technology'
Munich School of Systemic Neurosciences

Swiss National Science Foundation (SNF)