title: Loss of cardiolipin leads to perturbation of mitochondrial and cellular iron homeostasis.
abstract: Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays a critical role in mitochondrial bioenergetic functions. The importance of CL in human health is underscored by the observation that perturbation of CL biosynthesis causes the severe genetic disorder Barth syndrome. To fully understand the cellular response to the loss of CL, we carried out genome-wide expression profiling of the yeast CL mutant crd1Δ. Our results show that the loss of CL in this mutant leads to increased expression of iron uptake genes accompanied by elevated levels of mitochondrial iron and increased sensitivity to iron and hydrogen peroxide. Previous studies have shown that increased mitochondrial iron levels result from perturbations in iron-sulfur (Fe-S) cluster biogenesis. Consistent with an Fe-S defect, deletion of ISU1, one of two ISU genes that encode the mitochondrial Fe-S scaffolding protein essential for the synthesis of Fe-S clusters, led to synthetic growth defects with the crd1Δ mutant. We further show that crd1Δ cells have reduced activities of mitochondrial Fe-S enzymes (aconitase, succinate dehydrogenase, and ubiquinol-cytochrome c oxidoreductase), as well as cytosolic Fe-S enzymes (sulfite reductase and isopropylmalate isomerase). Increased expression of ATM1 or YAP1 did not rescue the Fe-S defects in crd1Δ. These findings show for the first time that CL is required for Fe-S biogenesis to maintain mitochondrial and cellular iron homeostasis.
authors.affiliation: Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202, USA.
authors.forename: Vinay A
authors.initials: VA
authors.lastname: Patil
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fox
authors.forename: Vishal M
authors.initials: VM
authors.lastname: Gohil
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Winge
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Greenberg
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D007535:Isomerases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D050864:Sulfite Reductase (NADPH) / Q000235:genetics / Q000378:metabolism
chemical_list: D002308:Cardiolipins; C121520:ISU1 protein, S cerevisiae; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D006861:Hydrogen Peroxide; D007501:Iron; D013385:Succinate Dehydrogenase; D050864:Sulfite Reductase (NADPH); C494326:sulfite reductase (NADPH), S cerevisiae; D000154:Aconitate Hydratase; C032241:isopropylmalate isomerase; D007535:Isomerases; D014450:Electron Transport Complex III