Early Loss of Cerebellar Mitochondria May Drive Disease in FA, Mouse Study Suggests

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by Magdalena Kegel |

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The production and function of mitochondria — cellular power plants that convert nutrients to energy — is impaired in the cerebellum of the brain in early stages of a Friedreich’s ataxia mouse model, researchers at Children’s Hospital of Philadelphia report.

The findings support the idea that the cerebellar disease in patients with Friedreich’s ataxia is caused by the loss of functional mitochondria in this brain region.

The study, “Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia,” was published in the journal Disease Models & Mechanisms.

The study is among the many attempting to explain how the loss of frataxin protein causes Friedreich’s ataxia. Frataxin is a mitochondrial protein. But although researchers have known this for a long time, they still lack a detailed understanding of how its loss causes disease.

Such knowledge may be invaluable in developing treatments for the condition.

One of the problems in studying early disease changes is that affected tissues, such as the heart or brain, can usually only be obtained from deceased patients who were in advanced stages of disease.

Also, earlier mouse models progressed too rapidly to study early mechanisms.

The research team used a newer mouse model with slowly developing disease to study mitochondrial changes in the animals’ cerebellum. The cerebellum coordinates movement, and disease in this brain area causes ataxia.

They discovered that frataxin levels became progressively lower as the mice grew. Meanwhile, the levels of a factor crucial for the production of new mitochondria decreased in a similar way — levels became lower as mice aged.

Researchers noted a loss of the mitochondrial factor before symptoms emerged, and the reduction continued after the onset of FA symptoms. Other mitochondrial factors were, likewise, reduced in a progressive manner.

Using a fluorescent gene marker, the team could conclude that the mice appeared to have fewer mitochondria in their brains.

Mitochondria also showed abnormalities in the enzymes guarding energy production.

Researchers said it is possible that the decreased levels of the factor driving mitochondrial production may cause a progressive reduction of frataxin.

While these insights are key to the understanding of Friedreich’s ataxia processes, researchers said that mitochondrial production deficits could potentially also serve as a marker of disease progression in Friedreich’s ataxia patients.

“Taken together, our findings reveal early mitochondrial biogenesis deficits as a potential pathogenic mechanism, and also as a potential biomarker and therapeutic target in [Friedreich’s ataxia] patients,” they concluded.