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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)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Progressive Multiple-sclerosis; High-dose Biotin; Isocitrate Dehydrogenase; Neurodegeneration; Mitochondria; Mechanisms; Cancer; Dysfunction; Metabolism; Neurons
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Zeitschrift Nature metabolism
Quellenangaben Band: 5, Heft: 8, Seiten: 1364-1381 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Förderungen 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)