Closing Leaky Mitochondria Halts Behavioral Problems in Fragile X, Study Suggests

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by Patricia Inacio PhD |

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Shortage of energy due to leaky mitochondria — the powerhouses of cells — contributes to behavioral abnormalities in fragile X syndrome, a study has found.

Closure of the leaky mitochondrial membrane with a form of a Parkinson’s disease medicine boosted energy production and reversed autism-like behaviors in mouse models of fragile X.

The study, “ATP Synthase c-Subunit Leak Causes Aberrant Cellular Metabolism in Fragile X Syndrome,” was published in the journal Cell.

Fragile X, the most common inherited cause of autism and intellectual disability, is caused by mutations in the FMR1 gene. The mutations result in failure to produce a protein called FMRP, also known as fragile X mental retardation protein.

The lack of FMRP impairs the function of mitochondria. In a recent study using a mouse model of fragile X, researchers at Yale University showed that mitochondria in neurons fail to produce the necessary levels of energy.

Now they have found that energy shortage is caused by mitochondria’s leaky inner membrane. Specifically, the scientists discovered abnormally high levels of ATP synthase enzyme, a key channel protein in this membrane and required for the production of ATP — the major source of energy in cells — contributing to defects in mitochondrial function.

This alteration was linked with impairments in synapses — the junctions between two nerve cells that allow them to communicate — that led to defects in memory, learning, and brain development in mouse models of fragile X.

“This leaky membrane is making the process of ATP production inefficient,” Elizabeth Ann Jonas, MD, a professor of internal medicine and neuroscience, and the study’s senior author, said in a Yale press release.

“In Fragile X neurons, the synapses fail to mature during development. The synapses remain in an immature state and this seems to be related to their immature metabolism,” she said.

The investigators tested whether closing the leak to boost the efficiency of ATP production would lessen behavioral abnormalities.

They first saw that nerve cells treated with an ATP synthase inhibitor named dexpramipexole (Dex) — a form of the common Parkinson’s therapy Mirapex ER (pramipexole) and previously tested as a treatment for amyotrophic lateral sclerosis — increased the levels of ATP.

Two-day treatment with Dex also reversed autistic-like behaviors, namely excessive time spent grooming and compulsive shredding of the animals’ nests. The treatment also reduced hyperactivate behaviors.

“We find that inhibition of the ATP synthase leak allows for the maturation of synapses and normalizes autistic behaviors in a mouse model of [fragile X],” the team wrote.

Jonas and her team now intend to further test the effectiveness of this and other leak-closing therapies for improving learning.

The lab is conducting a study assessing the role of leaky membranes in memory formation. Findings could pave the way for novel therapeutics for fragile X and autism, as well as for Alzheimer’s disease.

“Mitochondria are making ATP in synapses all throughout life,” said Jonas. “We think mitochondrial leak closure may be one of the first responses to neuronal activity when you form a memory and this could be required for the changes that lead to long-term memory formation.”

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