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Mitochondria, ROS and yeast ageing

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In this presentation I will talk about a yeast deletion mutant in the gene AFO1 , coding for a mitochondrial ribosomal protein, which confers respiratory deficiency, resistance to several oxidants, and a marked increase of the replicative lifespan. The mutant grows rapidly on glucose media due to secondary mutations which are selected for during growth. The mutant displays an extraordinarily low level of oxygen radicals. We show that the mutant strain grows rapidly and produces ethanol and biomass on glucose with a kinetics comparable to wild type, in stark contrast to a bona fide ethidium bromide induced rho-zero strain, which grows slowly. The growth phenotypes were shown to be the same in three quite different genetic backgrounds, two of them completely prototrophic, and seem to be dependent on secondary mutations in ATP3 . In an evolutionary experiment starting with a diploid rho-zero strain, the fast growing respiratory deficient strains contained dominant point mutations in ATP3 , which after PCR cloning and introduction into rho-zero strains induced rapid growth. Adenine nucleotide levels are not significantly different in the fast and slow-growing strains. A hypothesis not contradicting these findings is that the slow growth of ordinary rho-zero strains depends on a lack of energizing the mitochondria, not on a general low level of ATP . The mutations in ATP3 could act by increasing the ATPase activity and thereby increasing the membrane potential of the mitochondria, which could improve the efficiency of essential metabolic pathways that have to take place in mitochondria. In the second part of the talk I will present the identification and partial functional analysis of YNO1 , a gene coding for a yeast NADPH oxidase. The enzyme is located in the ER and is responsible for the high level of superoxide production in cox4-deletion strains in the post-diauxic phase. This depends on the translocation of active Ras2 to the mitochondria. In wild type cells under growth conditions on glucose, Yno1 is expressed at a low level, but is needed for the formation of actin cables. The yno1 deletion mutant confers hypersensitivity to wiskostatin and latrunculinB, two drugs that inhibit actin cable formation. Inhibition of the actin cables can be overcome by adding a low non-toxic concentration of hydrogen peroxide. Overexpression of YNO1 leads to apoptosis, short chronological lifespan and increased budding index in the stationary phase. The function of Yno1 was further studied by testing phenotypes of yno1 with deletion mutants in the actin regulatory network.

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