Mouse model shows iron imbalance in FA varies by tissue and age: Study
Genetic disease characterized by defects in how cells regulate mineral
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Friedreich’s ataxia (FA) is characterized by defects in how cells regulate iron, which seem to differ by tissue and over time, according to a study using a new mouse model designed to better reflect the human disease.
Specifically, animals showed an early buildup of iron in the brain and a later buildup in the liver, while iron levels remained normal in the heart — a result that differs from findings in earlier mouse models.
“The obtained results indicate that alterations in iron homeostasis are age-dependent and tissue-specific, with early iron accumulation in the [brain] and a later accumulation in the liver,” researchers wrote.
The study, “Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis,” was published in iScience.
New mouse model better mimics human condition
FA is a genetic disease caused by mutations in the gene that provides instructions for making frataxin, a protein involved in cellular energy production. People with FA produce much lower amounts of frataxin than normal, and this deficiency is believed to drive disease symptoms such as coordination problems and heart damage.
However, scientists still don’t fully understand the specific molecular mechanisms by which frataxin deficiency causes FA symptoms.
While previous research has suggested that frataxin deficiency disrupts iron metabolism, much of that earlier work relied on knockout mice completely lacking frataxin. Yet, unlike knockout mice, most people with FA still produce small amounts of the protein, raising questions about whether those models accurately reflect what happens in patients.
To better mimic the human condition, the researchers created a new mouse model that produces very low levels of frataxin rather than none at all. The model, called FXNI151F, allowed them to study how partial frataxin deficiency affects iron regulation across the body.
“Using the FXNI151F murine model, we have analyzed for the first time the disturbances to mammalian iron [regulation] caused by [body-wide] partial frataxin deficiency, thus approaching the [disease-causing] conditions experienced by FA patients,” the researchers wrote.
Iron imbalance in FA emerges first in brain and then liver, results show
The experiments showed that FXNI151F mice had excess iron in the cerebellum, a brain region that helps with coordination and is characteristically impacted in FA. This was observed as early as 10 weeks of age and persisted through week 21.
The buildup of iron in this region was accompanied by reduced levels of IRP1, a protein that helps regulate iron levels within cells.
In contrast, iron levels in heart tissue were not significantly different from those seen in healthy mice. However, heart cells in the FA model showed increased levels of IRP2, another protein involved in iron regulation, in 21-week-old mice — but not in younger animals.
Changes in the liver followed a different pattern. Older FXNI151F mice showed increased iron levels and reduced IRP1 protein in this organ, but these changes were not seen in younger animals. The buildup of iron in the liver was also more pronounced in female mice, and this sex difference occurred in both FA and healthy animals.
Overall, the results indicate that iron imbalance in FA emerges first in the brain and later in the liver, and that the process varies by tissue.
The scientists said these findings were broadly similar to what’s been previously reported using knockout mice, but with some important differences. For example, previous models suggested that iron accumulates in the heart, which was not observed in the new model designed to more closely mirror the biology of FA in people.
According to the researchers, these insights may help scientists better understand how frataxin deficiency disrupts iron metabolism and guide efforts to develop new therapies for FA.
