Frataxin depletion in yeast triggers up-regulation of iron transport systems before affecting iron-sulfur enzyme activities.
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 up-regulation 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.
Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Institut de Recerca Biomèdica de Lleida, Universitat de Lleida, 25008 Lleida, Spain.
Armando
A
Moreno-Cermeño
Elia
E
Obis
Gemma
G
Bellí
Elisa
E
Cabiscol
Joaquim
J
Ros
Jordi
J
Tamarit
D000154:Aconitate Hydratase / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D007477:Ions; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics* / Q000502:physiology; D007506:Iron-Sulfur Proteins / Q000737:chemistry*; D008345:Manganese / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010957:Plasmids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D015854:Up-Regulation; D000096923:Frataxin
D000154:Aconitate Hydratase; D027682:Cation Transport Proteins; D007477:Ions; D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D008345:Manganese; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin; C416343:Smf2 protein, S cerevisiae