TY - JOUR
T1 - Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions
AU - Tai, Yi-Heng
AU - Engels, Daniel
AU - Locatelli, Giuseppe
AU - Emmanouilidis, Ioanna
AU - Fecher, Caroline
AU - Theodorou, Delphine
AU - Müller, Stephan A
AU - Licht-Mayer, Simon
AU - Kreutzfeldt, Mario
AU - Wagner, Ingrid
AU - de Mello, Natalia Prudente
AU - Gkotzamani, Sofia-Natsouko
AU - Trovò, Laura
AU - Kendirli, Arek
AU - Aljović, Almir
AU - Breckwoldt, Michael O
AU - Naumann, Ronald
AU - Bareyre, Florence M
AU - Perocchi, Fabiana
AU - Mahad, Don
AU - Merkler, Doron
AU - Lichtenthaler, Stefan F
AU - Kerschensteiner, Martin
AU - Misgeld, Thomas
N1 - © 2023. The Author(s).
PY - 2023/7/10
Y1 - 2023/7/10
N2 - 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.
AB - 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.
U2 - 10.1038/s42255-023-00838-3
DO - 10.1038/s42255-023-00838-3
M3 - Article
C2 - 37430025
SN - 2522-5812
JO - Nature Metabolism
JF - Nature Metabolism
ER -