Mitochondrial DNA instability in cells lacking aconitase correlates with iron citrate toxicity.
Aconitase, the second enzyme of the tricarboxylic acid cycle encoded by ACO1 in the budding yeast Saccharomyces cerevisiae, catalyzes the conversion of citrate to isocitrate. aco1Δ results in mitochondrial DNA (mtDNA) instability. It has been proposed that Aco1 binds to mtDNA and mediates its maintenance. Here we propose an alternative mechanism to account for mtDNA loss in aco1Δ mutant cells. We found that aco1Δ activated the RTG pathway, resulting in increased expression of genes encoding citrate synthase. By deleting RTG1, RTG3, or genes encoding citrate synthase, mtDNA instability was prevented in aco1Δ mutant cells. Increased activity of citrate synthase leads to iron accumulation in the mitochondria. Mutations in MRS3 and MRS4, encoding two mitochondrial iron transporters, also prevented mtDNA loss due to aco1Δ. Mitochondria are the main source of superoxide radicals, which are converted to H2O2 through two superoxide dismutases, Sod1 and Sod2. H2O2 in turn reacts with Fe(2+) to generate very active hydroxyl radicals. We found that loss of Sod1, but not Sod2, prevents mtDNA loss in aco1Δ mutant cells. We propose that mtDNA loss in aco1Δ mutant cells is caused by the activation of the RTG pathway and subsequent iron citrate accumulation and toxicity.
Department of Biological Sciences, University of New Orleans, New Orleans, LA 70148, USA.
Muhammad A
MA
Farooq
Tammy M
TM
Pracheil
Zhejun
Z
Dong
Fei
F
Xiao
Zhengchang
Z
Liu
D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2
D000154:Aconitate Hydratase; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D027682:Cation Transport Proteins; D004272:DNA, Mitochondrial; D035941:Iron Regulatory Protein 1; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000099156:Superoxide Dismutase 2; C066985:MRS3 protein, S cerevisiae; C066986:MRS4 protein, S cerevisiae; C079378:RTG1 protein, S cerevisiae; C104438:RTG3 protein, S cerevisiae