Defective
iron utilization leading to either systemic or regional misdistribution of the
metal has been identified as a critical feature of several different disorders.
Iron concentrations can rise to toxic levels in mitochondria of excitable cells, often leaving the cytosol
iron-depleted, in some forms of neurodegeneration with brain accumulation (NBIA) or following mutations in genes associated with mitochondrial functions, such as ABCB7 in
X-linked sideroblastic anemia with
ataxia (
XLSA/A) or the genes encoding
frataxin in
Friedreich's ataxia (FRDA). In
anemia of
chronic disease (ACD),
iron is withheld by macrophages, while
iron levels in extracellular fluids (e.g., plasma) are drastically reduced. One possible therapeutic approach to these diseases is
iron chelation, which is known to effectively reduce multiorgan
iron deposition in
iron-overloaded patients. However,
iron chelation is probably inappropriate for disorders associated with misdistribution of
iron within selected tissues or cells. One
chelator in clinical use for treating
iron overload,
deferiprone (
DFP), has been identified as a reversed
siderophore, that is, an agent with
iron-relocating abilities in settings of regional
iron accumulation.
DFP was applied to a cell model of FRDA, a paradigm of a disorder etiologically associated with cellular
iron misdistribution. The treatment reduced the mitochondrial levels of labile
iron pools (LIP) that were increased by
frataxin deficiency.
DFP also conferred upon cells protection against oxidative damage and concomitantly mediated the restoration of various metabolic parameters, including
aconitase activity. Administration of
DFP to FRDA patients for 6 months resulted in selective and significant reduction in foci of brain
iron accumulation (assessed by T2* MRI) and initial functional improvements, with only minor changes in net body
iron stores. The prospects of
drug-mediated
iron relocation versus those of chelation are discussed in relation to other disorders involving
iron misdistribution, such as ACD and
XLSA/A.