Mitochondrial Dysfunction in Neuron-supporting Cells May Lead to Fragile X

The function and components of mitochondria — the cells’ powerhouses — are significantly reduced in the cerebral cortex and in neuron-supporting cells of a mouse model of fragile X syndrome, a study shows.

In addition, these mitochondrial abnormalities were associated with lower levels of mitochondrial components inside small fatty vesicles used by cells to transport molecules between them.

The findings suggest that mitochondrial dysfunction in these neuron-supporting cells, called astrocytes, may contribute to the development of fragile X, but further studies are needed to clarify this, researchers said.

The study, “Depletion of Mitochondrial Components from Extracellular Vesicles Secreted from Astrocytes in a Mouse Model of Fragile X Syndrome,” was published in the International Journal of Molecular Sciences and was conducted by a team in South Korea.

Fragile X, the most common single genetic cause of autism spectrum disorder, is caused by low-to-no levels of the fragile X mental retardation protein (FMRP) due to mutations in the FMR1 gene.

Produced by neurons and astrocytes, FMRP regulates the production of several other proteins, many of which are involved in the development and maturation of synapses — the site of near contact between nerve cells that allows them to communicate.

Previous studies have highlighted that FMRP deficiency leads to mitochondrial malformations and dysfunction in developing neurons, resulting in insufficient energy production and impairing both synapse and nerve cell maturation and health.

However, whether low levels of FMRP also promote mitochondrial dysfunction in astrocytes remains unclear.

Increasing evidence suggests that mitochondria and their functional components may be transferred between cells under disease conditions, likely as a mechanism to rapidly relieve mitochondrial damage.

Several studies have highlighted that “one of the most effective forms of communication between astrocytes and neurons occurs through [small fatty vesicles],” the researchers wrote.

In normal conditions, vesicles released by astrocytes have neuroprotective effects, and a previous study showed that astrocytes can release mitochondria-containing vesicles, suggesting that these supporting cells may use this ability to lessen mitochondrial dysfunction in neighboring neurons.

Here, the scientists evaluated mitochondrial function and components, as well as their potential transport through small vesicles, in the cerebral cortex and in astrocytes of a mouse model of fragile X that lacks the FMR1 gene. The cerebral cortex is the outermost layer of the brain and is involved in higher cognitive functions, such as problem-solving, thinking, and planning.

Results showed that mice lacking the FMR1 gene had significantly lower amounts of proteins essential for mitochondrial function in both the cerebral cortex and in astrocytes, compared with healthy mice.

These abnormalities were accompanied by a drop in the levels of mitochondria formation markers in the mouse cortex, and by deficient mitochondrial function and abnormal distribution of vimentin intermediate filaments in astrocytes. (These structural filaments control mitochondria’s location and function within cells.)

Further analyses revealed significantly fewer mitochondrial components inside small vesicles secreted by cells in the cerebral cortex and by astrocytes from affected mice, compared with healthy mice.

These findings confirmed that mitochondrial proteins are delivered through small vesicles and suggest that mitochondrial dysfunction in astrocytes is associated with the development of fragile X.

Notably, the team hypothesized that mitochondrial proteins in astrocytes lacking FMRP may be removed from these transporting vesicles before their secretion.

“Further studies are needed to determine the precise mechanism(s) for the observed decrease in mitochondrial proteins, which could reflect a deficit in the intracellular trafficking from mitochondria to [vesicles] or disruption of [vesicles] formation,” the researchers wrote.

They further said that future research also should focus on the potential role of these astrocyte-derived vesicles in the progression of fragile X.

In addition, measuring the levels of mitochondrial proteins in these tiny vesicles may help to diagnose developmental disorders associated with mitochondrial dysfunction, such as fragile X and autism spectrum disorders, the team said.