Perspectives on the mitochondrial etiology of replicative aging in yeast Ana Ugidos, Thomas Nyström, Antonio Caballero * Department of Cell and Molecular Biology, Göteborg University, Medicinaregatan 9C, 413 90 Göteborg, Sweden article info Article history: Received 2 December 2009 Received in revised form 15 January 2010 Accepted 2 February 2010 Available online 12 February 2010 Keywords: Aging Mitochondria Yeast Caloric restriction Replicative life span abstract In a now classical paper, Denham Harman suggested that free radicals produced during mitochondrial respiration cause cumulative oxidative damage, resulting in aging and age-related disorders and pathol- ogies. Proponents of this hypothesis have focused their attention, not surprisingly, on mitochondria argu- ing that these organelles may serve as the biological clock for aging. Indeed, work on many models, including filamentous fungi, nematodes, and mammals have revealed that age-dependent reorganiza- tions of the mitochondrial DNA (mtDNA) may play a central role in the aging of these organisms. Further- more, genetic alterations of mitochondrial function may either shorten or extend life span. In this paper, we focus on the role of mitochondria in the replicative aging of yeast mother cells, whether this role of mitochondria is really a linked to altered ROS production and/or respiration, and highlight some impor- tant questions that remain to be answered. Ó 2010 Elsevier Inc. All rights reserved. 1. Introduction The maintenance of mitochondrial homeostasis is of central importance to fitness and health as mitochondria are key players in ATP production, signaling, and programmed cell death processes (Loeb et al., 2005). Disturbed mitochondrial functions may increase disease susceptibility, and could also mediate critical disease symptoms. For instance, altered control of mitochondrial energy and ROS homeostasis play central roles in metabolic syndrome, obesity, and diabetes. In addition, oxidative protein damage and neurological disorders, such as Alzheimer’s and Parkinson’s, are intimately linked to dysfunctional mitochondria. A holistic under- standing of the design principles of mitochondrial quality control and their homeostatic control circuits, how they interact, and how they affect signaling pathways targeting nuclear genes that feed-back regulate mitochondrial performance, is therefore of great interest both for basic science and for health-care through the development of new therapies. The ‘‘mitochondrial theory of aging”, which expands on the ‘‘free radical theory of aging” suggests that mitochondrial ROS pro- duction is an important culprit also in the aging process (Harman, 1972). Oxidative attack of mitochondrial DNA (mtDNA) has been suggested to be particularly important since accumulation of mtDNA mutations may, in turn, lead to elevated production of ROS and a feed-back catastrophe (Loeb et al., 2005). In support of this notion, introducing an error-prone mtDNA polymerase (Pol- c) in mice results in a phenotype that resembles premature aging (Kujoth et al., 2005), although recent studies have called these findings into question (Khrapko et al., 2006). Alteration of other mitochondrial functions can extend, rather than shorten, life span. The first experimental evidence for mitochondria-dependent life span extension mechanisms demonstrated that specific mitochon- drial inhibitors retard aging of the filamentous fungi Podospora anserina (Marcou, 1961). Similarly, reducing the expression of, or mutating, specific genes encoding mitochondrial proteins can ex- tend the life span of worms and flies (Copeland et al., 2009; Lee et al., 2003). In addition, ectopic overproduction of the mitochon- drial Mn-superoxide dismutase (Mn-SOD2) has been demon- strated to extend the life span of adult Drosophila melanogaster flies (Sun et al., 2002). However, a similar approach has found that deleting the mitochondrial Mn-SOD2 actually extends life span of the worm (Van Raamsdonk and Hekimi, 2009). Thus, at present it is unclear whether mitochondrial ROS production and oxidative damage form integral parts of a conserved aging pathway. The aim of this article is to briefly summarize what is known about the mitochondrial etiology of replicative aging in yeast, and pinpoint important questions and perspectives to approach in the future. 2. Yeast replicative aging Mitosis in the yeast Saccharomyces cerevisiae is distinctively asymmetrical and includes mother cell-specific aging (Steinkraus et al., 2008). During progressive cell divisions, the mother cell undergoes age-related changes, including an increased generation time, increase in size, decline in mating ability, accumulation of bud scars on the cell wall, nucleolar fragmentation, mitochondrial 0531-5565/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2010.02.002 * Corresponding author. E-mail address: antonio.caballero@cmb.gu.se (A. Caballero). Experimental Gerontology 45 (2010) 512–515 Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero