Fixing frataxin: ‘ironing out’ the metabolic defect in Friedreich's ataxia

Abstract

The metabolically active and redox-active mitochondrion appears to play a major role in the cellular metabolism of the transition metal, iron. Frataxin, a mitochondrial matrix protein, has been identified as playing a key role in the iron metabolism of this organelle due to its iron-binding properties and is known to be essential for iron-sulphur cluster formation. However, the precise function of frataxin remains elusive. The decrease in frataxin expression, as seen in the inherited disorder Friedreich's ataxia, markedly alters cellular and mitochondrial iron metabolism in both the mitochondrion and the cell. The resulting dysregulation of iron trafficking damages affects tissues leading to neuro-and cardiodegeneration. This disease underscores the importance of iron homeostasis in the redox-active environment of the mitochondrion and the molecular players involved. Unravelling the mechanisms of altered iron metabolism in Friedreich's ataxia will help elucidate a biochemical function for frataxin. Consequently, this will enable the development of more effective and rationally designed treatments. This review will focus on the emerging function of frataxin in relation to the observed alterations in mitochondrial iron metabolism in Friedreich's ataxia. Tissue-specific alterations due to frataxin loss will also be discussed, as well as current and emerging therapeutic strategies.

Cellular iron uptake, trafficking and metabolism: Key molecules and mechanisms and their roles in disease

“…and it is involved in regulating systemic iron homeostasis by an as-yet-unknown mechanism [3,62,79,80]. In addition, evidence supports its role as an essential factor in ISC biogenesis [79].…”

“…In addition, evidence supports its role as an essential factor in ISC biogenesis [79]. Crucially, frataxin-deficiency causes the rare, but severe neuro-and cardio-degenerative disease, FRDA, which is due to a GAA-repeat expansion in intron 1 of FRDA gene that encodes for frataxin [81].…”

“…Crucially, frataxin-deficiency causes the rare, but severe neuro-and cardio-degenerative disease, FRDA, which is due to a GAA-repeat expansion in intron 1 of FRDA gene that encodes for frataxin [81]. Frataxin is a vital protein that is highly expressed in tissues rich in mitochondria e.g., heart and neurons [82], with total deletion being embryonically lethal [83].Most suggested functions for frataxin, a mitochondrial matrix protein [79,81], relate to iron-binding and maintenance of mitochondrial iron metabolism (Fig. 6).…”

Iron chelation in the treatment of neurodegenerative diseases

“…Pathological amounts of iron supposedly accumulate in the mitochondria in FRDA, apparently leading to a deficiency of mitochondrial ironsulphur cluster-containing proteins such as aconitase [87][88][89][90]. The respiratory chain electron transporters involving complex I-III are inhibited, resulting in decreased energy production and increased free radical formation [91] which may ultimately lead to oxidative stress-induced activation of the intrinsic apoptotic pathway [92].…”

Mitigation of myocardial ischemia-reperfusion injury via HIF-1α-frataxin signaling

“…Frataxin is an evolutionary-conserved mitochondrial matrix protein whose putative functions are thought to limit ROS production and oxidative stress (1). It is heavily implicated in the biogenesis of Fe-S, which are critical cofactors involved in ATP generation, intracellular oxygen, iron, and ROS sensing, and the replication and maintenance of the nuclear genome (10).…”