Impaired mitochondrial function protects against free radical-mediated cell death.
Free radical damage can have fatal consequences. Mitochondria carry out essential cellular functions and produce high levels of reactive oxygen species (ROS). Many agents also generate ROS. Using the yeast Saccharomyces cerevisiae as a eukaryotic model, the role of functional mitochondria in surviving free radical damage was investigated. Respiratory-deficient cells lacking mitochondrial DNA (rho(0)) were up to 100-fold more resistant than isogenic rho(+) cells to killing by ROS generated by the bleomycin-phleomycin family of oxidative agents. Up to approximately 90% of the survivors of high oxidative stress lost mitochondrial function and became "petites." The selective advantage of respiratory deficiency was studied in several strains, including DNA repair-deficient rad52/rad52 and blm5/blm5 diploid strains. These mutant strains are hypersensitive to lethal effects of free radicals and accumulate more DNA damage than related wild-type strains. Losses in mitochondrial function were dose-dependent, and mutational alteration of the RAD52 or BLM5 gene did not affect the resistance of surviving cells lacking mitochondrial function. The results indicate that inactivation of mitochondrial function protects cells against lethal effects of oxygen free radicals.
Davermann
Darlene
D
Department of Microbiology and Immunology, City University of New York Medical School/Sophie Davis School of Biomedical Education and Graduate Programs in Biochemistry and Biology, New York 10031, USA.
Martinez
Marcia
M
McKoy
Judith
J
Patel
Nima
N
Averbeck
Dietrich
D
Moore
Carol Wood
CW
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004271:DNA, Fungal / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005609:Free Radicals / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D016296:Mutagenesis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010692:Phleomycins / Q000494:pharmacology; D051721:Rad52 DNA Repair and Recombination Protein; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins
D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D004271:DNA, Fungal; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D005609:Free Radicals; D010692:Phleomycins; C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D001761:Bleomycin