Boosting energy production in nerve fibers may help treat MS

In multiple sclerosis (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.

The study, “Targeting the TCA cycle can ameliorate widespread axonal energy deficiency in neuroinflammatory lesions,” published in Nature Metabolism.

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MS is caused by inflammation in the brain and spinal cord, which damages axons, or nerve fibers. While this general mechanism is well established, it remains unclear exactly how inflammation leads to axon damage at the molecular level.

One proposed idea is that inflammation may lead to impaired energy production in axons. Normally, axons require a lot of energy to provide power for sending electrical signals, and accumulating research has shown that energy production in axons is reduced in MS and other neurological diseases.

Here, researchers used advanced imaging and molecular analysis tools to examine how inflammation might lead to problems with energy production in axons using mice with experimental autoimmune encephalitis (EAE), a mouse model commonly used to study MS.

In an initial set of experiments, the researchers demonstrated that axons in areas of acute or chronic inflammation showed a marked reduction in levels of ATP, essentially cellular energy currency. That supports the idea that inflamed axons have impaired energy production.

The scientists noted that the reduction in ATP was found not only in axons that showed obvious signs of damage, but also in nerve fibers that otherwise looked healthy.

Theoretically, the reduction in energy production in axons could be due to the dysfunction of mitochondria, the so-called powerhouse of the cell. However, when the researchers looked for signs of mitochondrial dysfunction in axons, they found that only axons showing obvious signs of damage had impaired mitochondrial function. Normal-looking axons appeared to have normal mitochondrial function, even though the researchers had already established that these normal-looking axons had reduced energy production.

“Taken together, these experiments indicate that overt dysregulation of [mitochondrial function] are rather late events during inflammatory axon degeneration,” the researchers wrote. This implies that other mechanisms and not mitochondrial ones must be the cause of reduced energy production at earlier disease stages.

When a cell breaks down sugar to produce energy, the sugar molecule first enters into a molecular pathway called the tricarboxylic acid cycle — the TCA cycle, also known as the Krebs cycle or the citric acid cycle. The TCA cycle itself generates a small amount of cellular energy, and the products from the cycle are then used by mitochondria to produce more energy.

In further mouse experiments, the researchers found that inflamed axons showed markedly lower levels of several critical enzymes in the TCA cycle, including a protein called IDH3, which is a rate-limiting enzyme. That means that levels of this enzyme control how quickly the pathway can function.

“Neuroinflammation caused a marked alteration in the expression of TCA cycle enzymes, including the rate-limiting enzyme Idh3, which likely hinders neuronal mitochondria from generating sufficient amounts of” energy, the researchers wrote.

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The team also conducted analyses of brain tissue collected from autopsies of seven people with MS. Consistent with the mouse experiments, the researchers found reduced levels of TCA enzymes in inflamed axons.

“Taken together, our findings suggest that TCA cycle disruption is a persistent neuronal change during MS lesion formation and progression,” they wrote.

The results imply that boosting the level of TCA enzymes, particularly the rate-limiting IDH3, might help to normalize energy production in inflamed axons.

To test this idea, the researchers used a gene therapy to express high levels of Idh3 in the axons of EAE mice.

Boosting IDH3 levels led to a marked increase in axons’ energy production, as evidenced by higher levels of ATP, the results showed. In addition, increasing levels of another TCA enzyme called MDH2, which normally functions closely with Idh3, escalated the axons’ energy production.

The researchers noted, however, that increasing levels of either of these individual TCA enzymes did not restore energy production to levels seen in healthy mice, and that treated axons still showed signs of damage. This suggests that “a full rectification of these neuroenergetic deficits will likely require a manipulation of either a master regulator or multiple enzyme targets in parallel,” they said.

“Thus, while the data presented here provide proof of the principle for TCA cycle targeting, they probably do not yet foreshadow a true translational strategy,” the scientists added, emphasizing a need for more research working toward developing treatments based on these concepts.

[These findings suggest that] targeting the TCA cycle may represent a novel strategy to protect the cells against mitochondrial dysfunction in multiple sclerosis.

In an editorial published alongside the study, a trio of scientists at the University of Bonn, in Germany, agreed that these findings suggest that “targeting the TCA cycle may represent a novel strategy to protect the cells against mitochondrial dysfunction in multiple sclerosis.”

The editorial also notes, however, that there are still unresolved questions. In particular, it remains unclear exactly how inflammation triggers a reduction in TCA enzymes in axons. A more detailed understanding of these mechanisms could allow for better understanding of how energy production is regulated in nerve cells and may open doors toward new treatment strategies, they said.