Adaptive aneuploidy protects against thiol peroxidase deficiency by increasing respiration via key mitochondrial proteins.
Aerobic respiration is a fundamental energy-generating process; however, there is cost associated with living in an oxygen-rich environment, because partially reduced oxygen species can damage cellular components. Organisms evolved enzymes that alleviate this damage and protect the intracellular milieu, most notably thiol peroxidases, which are abundant and conserved enzymes that mediate hydrogen peroxide signaling and act as the first line of defense against oxidants in nearly all living organisms. Deletion of all eight thiol peroxidase genes in yeast (∆8 strain) is not lethal, but results in slow growth and a high mutation rate. Here we characterized mechanisms that allow yeast cells to survive under conditions of thiol peroxidase deficiency. Two independent ∆8 strains increased mitochondrial content, altered mitochondrial distribution, and became dependent on respiration for growth but they were not hypersensitive to H2O2. In addition, both strains independently acquired a second copy of chromosome XI and increased expression of genes encoded by it. Survival of ∆8 cells was dependent on mitochondrial cytochrome-c peroxidase (CCP1) and UTH1, present on chromosome XI. Coexpression of these genes in ∆8 cells led to the elimination of the extra copy of chromosome XI and improved cell growth, whereas deletion of either gene was lethal. Thus, thiol peroxidase deficiency requires dosage compensation of CCP1 and UTH1 via chromosome XI aneuploidy, wherein these proteins support hydroperoxide removal with the reducing equivalents generated by the electron transport chain. To our knowledge, this is the first evidence of adaptive aneuploidy counteracting oxidative stress.
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Alaattin
A
Kaya
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Maxim V
MV
Gerashchenko
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
Inge
I
Seim
Oxidative Stress and Cancer, Institut de Biologie et Technologie-Saclay, FRE3377 Commisariat à l'Energie Atomique (CEA), Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, CEA-Saclay, F-91191 Gif Sur Yvette, France.
Jean
J
Labarre
Oxidative Stress and Cancer, Institut de Biologie et Technologie-Saclay, FRE3377 Commisariat à l'Energie Atomique (CEA), Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, CEA-Saclay, F-91191 Gif Sur Yvette, France.
Michel B
MB
Toledano
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; vgladyshev@rics.bwh.harvard.edu.
Vadim N
VN
Gladyshev
D000222:Adaptation, Physiological / Q000235:genetics*; D000782:Aneuploidy; D000968:Antimycin A / Q000494:pharmacology; D002872:Chromosome Deletion; D015825:Chromosomes, Fungal / Q000235:genetics*; D003578:Cytochrome-c Peroxidase / Q000235:genetics / Q000502:physiology; D004579:Electron Transport / Q000502:physiology*; D017353:Gene Deletion; D018628:Gene Dosage; D005800:Genes, Fungal; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D009840:Oligomycins / Q000494:pharmacology; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000502:physiology; D010544:Peroxidases / Q000172:deficiency / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*
D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009840:Oligomycins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; C116477:UTH1 protein, S cerevisiae; D012402:Rotenone; D000968:Antimycin A; D006861:Hydrogen Peroxide; D010544:Peroxidases; D003578:Cytochrome-c Peroxidase; D050862:Oxidoreductases Acting on Sulfur Group Donors; C479426:SRX1 protein, S cerevisiae
aneuploidy; oxidative stress; respiration; thiol peroxidase