Abstract
Mitochondrial dysfunction leads to the accumulation of reactive oxygen species (ROS) which is associated with cellular dysfunction, disease etiology, and senescence. Here, we used the eukaryotic model Saccharomyces cerevisiae, commonly studied for cellular aging, to demonstrate how defective mitochondrial function affects yeast replicative lifespan (RLS). We show that RLS of respiratory-deficient cells decreases significantly, indicating that the maintenance of RLS requires active respiration. The shortening of RLS due to mitochondrial dysfunction was not related to the accumulation of extrachromosomal ribosomal DNA circles, a well-known cause of aging in yeast. Instead, intracellular ROS and oxidatively damaged proteins increased in respiratory-deficient mutants. We show that, while the protein kinase A activity is not elevated, ROS generation in respiratory-deficient cells depends on RAS signaling pathway. The ER-localized NADPH oxidase Yno1 also played a role in producing ROS. Our data suggest that a severe defect in mitochondrial respiration accelerates cellular aging by disturbing protein homeostasis in yeast.
Highlights
Over the past few decades, the budding yeast Saccharomyces cerevisiae has contributed to the search for conserved elements in cellular aging [1, 2]
The loss of mitochondrial DNA is known to impact the longevity of cells in a strain-specific manner [37], Replicative lifespan (RLS) of BY4741 rho0 cells decreased by about 40% compared to that of wild-type cells (Fig 1A and 1B)
Through analysis of RLS in respiratorydeficient mutants, we found that mitochondrial respiration is required for the maintenance of RLS (Fig 1)
Summary
Over the past few decades, the budding yeast Saccharomyces cerevisiae has contributed to the search for conserved elements in cellular aging [1, 2]. Two distinct lifespan paradigms have been proposed. Chronological lifespan (CLS) is a model for the aging process of post-mitotic cells and measures the amount of time a cell can remain viable in a non-dividing state [3]. Replicative lifespan (RLS) is useful for understanding aging of dividing cells and defined as the number of mitotic divisions that each mother cell can undergo before senescence [4]. Three candidates are considered as important senescence factors. One of them is extrachromosomal ribosomal DNA circles (ERCs) formed by homologous recombination between ribosomal DNA repeats [5].
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