Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions.
Nat Metab
; 5(8): 1364-1381, 2023 08.
Article
en En
| MEDLINE
| ID: mdl-37430025
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Neuroinflamatorias
/
Esclerosis Múltiple
Límite:
Animals
Idioma:
En
Revista:
Nat Metab
Año:
2023
Tipo del documento:
Article
País de afiliación:
Alemania