Friedreich’s ataxia: a useful iron accumulation for cells…
In normal cells (A), iron import (through transferrin and its receptor) is sufficient to support the production of heme and iron-sulfur (Fe-S) clusters. The energy supplied to the cell is thus sufficient and most IRP1 proteins contain an Fe-S cluster.
In the absence of frataxin (B), the productions of heme and Fe-S clusters are less efficient. IRP1 devoid of Fe-S cluster then activates cellular iron import to support mitochondrial iron needs. Frataxin-deficient cells have less energy than a normal cell, but iron accumulation act as a compensatory mechanism that aims at increasing heme and Fe-S cluster productions.
Feb. 4, 2015
The mitochondrial iron accumulation observed in Friedreich’s ataxia was thought to be noxious. Hélène PUCCIO's team at the IGBMC has just demonstrated that this accumulation rather allows to partially compensate for the absence of frataxin. Resulting of a modification of the IRP1 protein activity, this accumulation supports the biogenesis of iron-sulfur clusters (Fe-S) and heme in mitochondria.
These important results regarding the cellular adaptation in the absence of frataxin also question the validity of therapeutic approaches aiming at neutralizing the cellular iron accumulation observed in Friedreich’s ataxia.
This work is published in Cell Metabolism on February 3rd, 2015.
Friedreich’s ataxia is a rare, very invalidating and incurable inherited disorder, which combines a progressive neurodegeneration and impaired heart function.
Due to mutations in the FXN gene, which codes for a mitochondrial protein called frataxin, this disease is characterized by an impaired activity of enzymes containing an iron-sulfur cluster (Fe-S) and by an accumulation of iron within the mitochondria.
As iron accumulation can possibly generate reactive oxygen species and thus damage the cell, it has been suspected for a long time to be important in the evolution of the disease. Hence, therapeutic approaches aiming at neutralizing the iron accumulation in cells were developed. There is however, to date, little evidence on the direct correlation between iron accumulation and progression of the disease in Friedreich’s ataxia patients.
IRP1, a witness and protagonist protein
Hélène Puccio's team thus decided to better understand both the fundamental mechanisms of iron deregulation in cells and how the iron accumulation influences cell function.
By characterizing mice having a frataxin deficiency in liver, an essential organ in the management of body iron, the researchers first showed that iron accumulation in mitochondria is related to the modification of the IRP1 protein activity (Iron regulatory protein 1): in the absence of frataxin, the production of Fe-S clusters is insufficient and most IRP1 proteins are devoid of a cluster. Yet, without its Fe-S cluster, IRP1 controls the import and the storage of iron in the cell, therefore providing a possible mechanistic explanation for the iron accumulation observed in cells of individuals with Friedreich's ataxia.
To clarify the role of IRP1, researchers then compared this mouse model with a second model in which both frataxin and IRP1 were depleted in the liver. They observed that the survival of the latter mice is reduced by half. By inducing a higher iron import and increasing iron availability, IRP1 supports the productions of Fe-S clusters and heme in the mitochondria, which are affected in the absence of frataxin. This compensatory mechanism is crucial to support the energy production needed for cell survival.
Through this work, Hélène Puccio's team established the key and specific role of IRP1 in the regulation of mitochondrial iron metabolism and the need to have sufficient available iron to sustain cell survival in Friedreich’s ataxia.