Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions, 2023, Yi-Heng Tai

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.

https://www.nature.com/articles/s42255-023-00838-3

 

Boosting energy production in nerve fibers may help treat MS.


In MS, inflammation leads to less energy production in nerve fibers by reducing the levels of enzymes in a key molecular pathway, called the TCA cycle, that cells use to generate energy, a new study shows.


These findings imply that boosting activity of the TCA cycle might one day offer potential treatment benefits in MS, according to researchers.

“Together, the results we present here expand our understanding of the molecular pathogenesis [development of disease] of immune-mediated mitochondrial [energy production] damage and propose new avenues for therapeutic intervention,” the team wrote.

https://multiplesclerosisnewstoday....gy-production-nerve-fibers-may-help-treat-ms/