Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions
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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. Neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP depletion, which precedes mitochondrial oxidation and calcium overload. This early axonal energy crisis is associated with impaired electron transport chain function, but also an upstream dysbalance of tricarboxylic acid (TCA) cycle enzymes. Isocitrate dehydrogenase 3 (Idh3), the rate limiting enzyme of the TCA cycle, is depleted in neuronal mitochondria in experimental models and in human MS lesions. Notably, viral overexpression of Idh3 can rectify the axonal energy deficits, suggesting that TCA cycle dysfunction in neuroinflammation may be amendable to therapy.
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Created: 5th Jul 2024 at 08:10
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Projects: SyNergy - Published Datasets
Institutions: Klinikum der Universität München
Projects: SyNergy - Published Datasets
Institutions: LMU
Projects: SyNergy - Published Datasets
Institutions: DZNE
Projects: SyNergy - Published Datasets, HTRA1
Institutions: Klinikum der Universität München
Projects: SyNergy - Published Datasets
Institutions: TUM
Public web page: Not specified
Organisms: Mus musculus, Rattus norvegicus, Homo sapiens, Macaca mulatta, Sus scrofa, Danio rerio
Submitter: Rainer Malik
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Assays: Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Affinity purification coupled with mass spectrometry proteomics (human), Bottom-up proteomics (mouse), Gel-based experiment (human), Phosphoproteomics / Bottom-up proteomics (mouse), Proximity-proteomics-based autophagosome content profiling (human), SWATH MS (human), SWATH MS (mouse), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (human, mouse), Shotgun proteomics (macaque), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (mouse), Shotgun proteomics (rat), Untargeted Proteomics (mouse)
Snapshots: Snapshot 1
Submitter: Rainer Malik
Assay type: Proteomics
Technology type: Technology Type
Investigation: Proteomics
Organisms: Mus musculus
SOPs: No SOPs
Data files: Mitoproteomics of neuronal mitochondria of EAE ...
Snapshots: No snapshots
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. Neuroinflammatory lesions in the mouse spinal cord cause widespread and persisting axonal ATP ...
Creator: Rainer Malik
Submitter: Rainer Malik
Investigations: Proteomics
Studies: Targeting the TCA cycle can ameliorate widespre...
Assays: Shotgun proteomics (mouse)
Abstract (Expand)
Authors: Y. H. Tai, D. Engels, G. Locatelli, I. Emmanouilidis, C. Fecher, D. Theodorou, S. A. Muller, S. Licht-Mayer, M. Kreutzfeldt, I. Wagner, N. P. de Mello, S. N. Gkotzamani, L. Trovo, A. Kendirli, A. Aljovic, M. O. Breckwoldt, R. Naumann, F. M. Bareyre, F. Perocchi, D. Mahad, D. Merkler, S. F. Lichtenthaler, M. Kerschensteiner, T. Misgeld
Date Published: 25th Aug 2023
Publication Type: Journal
PubMed ID: 37430025
Citation: Nat Metab. 2023 Aug;5(8):1364-1381. doi: 10.1038/s42255-023-00838-3. Epub 2023 Jul 10.