Several studies have suggested that the deregulation of iron processing in the organism is an important feature of frataxin deregulation, and consequently of Friedreich’s ataxia, according to a review study.
In the study, “Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?” researchers at Universitat de Lleida in Spain reviewed the role of iron in Friedreich’s ataxia and the potential use of iron-targeted strategies to treat it. The study was published in the journal Pharmaceuticals.
Friedreich’s ataxia is a genetic disorder caused by the loss or impaired activity of the frataxin protein. Although the protein’s function is still not fully clear, studies have suggested it may take part in the regulation of iron metabolism in cells.
Researchers have previously determined that frataxin-deficient cells accumulate iron, an observation that was subsequently confirmed by several other scientists. In fact, iron deposits or accumulation have been clearly reported in frataxin-deficient flies, cardiac muscles from frataxin-deficient mice, and Friedreich’s ataxia patients.
Further analysis has revealed that, in these situations, iron seems to accumulate in the form of tiny vesicles rather than in its normal aggregates of ferritin, a blood cell protein containing iron. This accumulation also only seems to affect some tissues, as it has been reported in the nervous system but not in fibroblasts or lymphoblasts (immune cells).
This impaired iron mechanism is believed to be due to an increased uptake of iron and a faulty mechanism in its transport; however, the details of the process are not yet completely understood.
Frataxin has been shown to interact with proteins that regulate iron transport not only within mitochondria but also in the outer mitochondria cell space.
But “some authors are skeptical about the existence of an extra mitochondrial form of frataxin,” the researchers said.
In accordance with the hypothesis that frataxin loss can lead to iron deregulation, several studies have suggested that rebalancing iron levels can ameliorate Friedreich’s ataxia manifestations.
It is believed that iron accumulation could be toxic as it may lead to increased production and buildup of oxygen reactive elements. Iron overload could also induce the production of some particular fatty molecules called sphingolipids, which could trigger the degeneration of nerve cells.
But the underlying mechanism involved in iron-related toxicity in Friedreich’s ataxia may be much more complex than initially suspected, involving different pathways based on the targeted tissue and cells.
Still, finding ways to target iron metabolism has been perceived as an attractive strategy to improve the outcome of Friedreich’s ataxia patients.
The use of iron chelators, such as deferiprone, has been proposed as a treatment to eliminate the excess iron accumulating in mitochondria. This compound can easily cross the blood-brain barrier and reach the central nervous system and mitochondria. In addition, since it is a chelator with a reduced affinity to iron, it could redistribute the iron in the body, reducing its targeted toxic effects.
Results from clinical trials have demonstrated that deferiprone holds therapeutic potential for Friedreich’s ataxia patients. But its effects were dependent on the dosage, as higher doses worsened patients’ symptoms.
“Low doses of the chelator would partially prevent the toxic effects that are caused by iron accumulation, while higher doses of deferiprone would compromise iron availability,” the team wrote.
Still, the clinical data suggested that deferiprone could be safely used at low doses and in combination with other therapies such as idebenone (a Q10 analogue), providing benefits for neurological function and heart hypertrophy related to Friedreich’s ataxia.
It remains unclear what the real contribution of iron accumulation is to Friedreich’s ataxia, “which could be related either to iron accumulation or to limited iron availability,” according to the researchers. Still, they believe that the underlying mechanism of the iron-related complex may be a consequence of “the alterations that are caused by frataxin deficiency.”
“This complexity may explain the limited effects of iron chelators on clinical trials, as these compounds would only prevent certain pathological mechanisms in a limited number of tissues,” they wrote.
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