Frataxin Depletion in Yeast Triggers Up-regulation of Iron Transport Systems before Affecting Iron-Sulfur Enzyme Activities

Abstract

The primary function of frataxin, a mitochondrial protein involved in iron homeostasis, remains controversial. Using a yeast model of conditional expression of the frataxin homologue YFH1, we analyzed the primary effects of YFH1 depletion. The main conclusion unambiguously points to the upregulation of iron transport systems as a primary effect of YFH1 down-regulation. We observed that inactivation of aconitase, an iron-sulfur enzyme, occurs long after the iron uptake system has been activated. Decreased aconitase activity should be considered part of a group of secondary events promoted by iron overloading, which includes decreased superoxide dismutase activity and increased protein carbonyl formation. Impaired manganese uptake, which contributes to superoxide dismutase deficiency, has also been observed in YFH1-deficient cells. This low manganese content can be attributed to the down-regulation of the metal ion transporter Smf2. Low Smf2 levels were not observed in AFT1/YFH1 double mutants, indicating that high iron levels could be responsible for the Smf2 decline. In summary, the results presented here indicate that decreased iron-sulfur enzyme activities in YFH1-deficient cells are the consequence of the oxidative stress conditions suffered by these cells.

Yap5 Protein-regulated Transcription of the TYW1 Gene Protects Yeast from High Iron Toxicity

“…Overexpressing Tyw1 in wild-type cells does not change iron levels in mitochondria or mitochondrial iron-sulfur cluster enzymes such as aconitase. Recently, it was suggested that increased activity of the iron regulon can occur in the absence of decreased mitochondrial Fe-S activity (23). How the membrane-spanning domain of S. cerevisiae Tyw1 affects the iron regulon is currently unknown.…”

Cells Lacking Pfh1, a Fission Yeast Homolog of Mammalian Frataxin Protein, Display Constitutive Activation of the Iron Starvation Response

“…However, it has also been demonstrated that restricting oxidative damage, either by decreasing ROS production (49) or by diminishing available iron (50), prevents aconitase inactivation. Furthermore, a conditional knockdown of YFH1 expression has allowed establishing the order of sequential events occurring upon frataxin depletion, indicating that induction of iron import is a primary event leading to the late inactivation of ISC-containing proteins (21). Our results suggest that the low levels of aconitase activity in cells lacking Pfh1 are a consequence of the earlier activation of the Php4 repressor, which in wild-type cells lowers expression of most ISC-containing proteins in an iron starvation-dependent manner.…”

“…However, studies on mice and yeast also show that the loss of ISCs precedes iron accumulation (9,20), so that the anomalies may not be a direct result of iron-induced oxidative damage. Furthermore, studies using an S. cerevisiae model of conditional expression of frataxin demonstrated that the primary consequence of frataxin depletion is to trigger upregulation of the iron transport system before affecting ironsulfur enzyme activities (21).…”

Loss of Cardiolipin Leads to Perturbation of Mitochondrial and Cellular Iron Homeostasis

“…Defects in mitochondrial Fe-S assembly lead to decreased maturation of both mitochondrial and cytosolic Fe-S proteins (20,28,(31)(32)(33)(34). In addition, excess mitochondrial iron causes oxidative damage to Fe-S clusters due to the formation of reactive oxygen species (ROS) (35)(36)(37).…”