Lack of DNA helicase Pif1 disrupts zinc and iron homoeostasis in yeast.
The Saccharomyces cerevisiae gene PIF1 encodes a conserved eukaryotic DNA helicase required for both mitochondrial and nuclear DNA integrity. Our previous work revealed that a pif1Δ strain is tolerant to zinc overload. In the present study we demonstrate that this effect is independent of the Pif1 helicase activity and is only observed when the protein is absent from the mitochondria. pif1Δ cells accumulate abnormal amounts of mitochondrial zinc and iron. Transcriptional profiling reveals that pif1Δ cells under standard growth conditions overexpress aconitase-related genes. When exposed to zinc, pif1Δ cells show lower induction of genes encoding iron (siderophores) transporters and higher expression of genes related to oxidative stress responses than wild-type cells. Coincidently, pif1Δ mutants are less prone to zinc-induced oxidative stress and display a higher reduced/oxidized glutathione ratio. Strikingly, although pif1Δ cells contain normal amounts of the Aco1 (yeast aconitase) protein, they completely lack aconitase activity. Loss of Aco1 activity is also observed when the cell expresses a non-mitochondrially targeted form of Pif1. We postulate that lack of Pif1 forces aconitase to play its DNA protective role as a nucleoid protein and that this triggers a domino effect on iron homoeostasis resulting in increased zinc tolerance.
Guirola
María
M
Departament de Genètica and Institut de Biomedicina, Universitat de Barcelona, Barcelona, Spain.
Barreto
Lina
L
Pagani
Ayelen
A
Romagosa
Miriam
M
Casamayor
Antonio
A
Atrian
Silvia
S
Ariño
Joaquín
J
D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D004843:Epistasis, Genetic / Q000187:drug effects; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology; D035941:Iron Regulatory Protein 1 / Q000096:biosynthesis* / Q000378:metabolism; D007527:Isoenzymes; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009994:Osmolar Concentration; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017262:Siderophores / Q000096:biosynthesis; D015032:Zinc / Q000378:metabolism* / Q000633:toxicity
D007502:Iron Chelating Agents; D007527:Isoenzymes; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D017262:Siderophores; D007501:Iron; C085463:PIF1 protein, S cerevisiae; D004265:DNA Helicases; D035941:Iron Regulatory Protein 1; D005978:Glutathione; D015032:Zinc