Abstract
Friedreich ataxia (FRDA) is a recessive disorder resulting from relative deficiency of the mitochondrial protein frataxin. Frataxin functions in the process of iron–sulfur (Fe–S) cluster synthesis. In this review, we update some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondrial changes occurring in FRDA and provide a methodology to monitor upcoming trials of frataxin restoration.
Highlights
Friedreich Ataxia (FRDA) is a recessive disorder beginning in childhood or juvenile years that causes progressive ataxia, dysarthria, loss of sensation, and loss of coordination [1,2,3]
The partial loss of frataxin in FRDA leads to deficient activity of such enzymes including aconitase, complex I and complex II [14,15,16], decreasing adenosine triphosphate (ATP) production and producing downstream dysfunction in mitochondrial activity and reactive oxygen species (ROS) production [17,18,19]
Frataxin deficiency leads to decreased levels of peroxisome proliferator-activated co-activator 1-α (PGC1α) in multiple models of FRDA, which, as reviewed previously, should cause specific metabolic abnormalities and decreased mitochondrial biogenesis
Summary
Friedreich Ataxia (FRDA) is a recessive disorder beginning in childhood or juvenile years that causes progressive ataxia, dysarthria, loss of sensation, and loss of coordination [1,2,3]. The partial loss of frataxin in FRDA leads to deficient activity of such enzymes including aconitase, complex I and complex II [14,15,16], decreasing adenosine triphosphate (ATP) production and producing downstream dysfunction in mitochondrial activity and reactive oxygen species (ROS) production [17,18,19].
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