Human babies are born young, independent of the age of their parents. Early studies revealed that daughter cells in yeast are also born young, with their full replicative lifespan, independent of the age of their mother cells. The identification of mother-daughter age asymmetry in budding yeast led to the hypothesis that aging determinants are asymmetrically distributed during yeast cell division. We obtained evidence that 1) there is heterogeneity in mitochondrial reactive oxygen species (ROS) within individual cells, 2) mitochondria with lower ROS, and are therefore fitter, are preferentially inherited by daughter cells, and 3) defects in mitochondrial quality control during inheritance perturbs mother-daughter age asymmetry. These studies indicate that mitochondria with low ROS are rejuvenation factors that contribute to daughter cell fitness and mother-daughter age asymmetry. We found that mitochondria that are destined for inheritance to daughter cells undergo actin-dependent movement from mother to daughter cells, and actin-dependent anchorage within the daughter cells. We also identified an actin-based mechanism for movement of cargos in the opposite direction, from buds to mother cells. We propose that these mechanisms contribute to mitochondrial quality control during inheritance, which in turn, contributes to mother-daughter age asymmetry. Interestingly, these same mechanisms have been implicated in segregation of mother-daughter age asymmetry determinants during yeast cell division, including clearance of oxidatively damaged protein aggregates from bud, and localization of the polarity factor, Bud6p in daughter cells. Equally important, we find that actin cables, the structures responsible for these segregation events, undergo an age-linked decline in organization and function. We propose that the decline in actin organization and function with age compromises segregation of age asymmetry determinants including high- and low-functioning mitochondria, which in turn, contributes to age-linked cellular dysfunction and loss of mother-daughter age asymmetry. Mitochondria have emerged as central regulators of lifespan, through their functions in aerobic energy mobilization, cellular metabolic control, and ROS production. The actin cytoskeleton has been implicated in enrichment of mitochondria at sites of polarized secretion in neurons, immune cells and yeast. In addition, age- associated declines in actin are linked to age-associated deficits in skeletal muscle function, epithelial wound healing, and T cell activation. We will study the mechanism underlying mitochondrial quality control during inheritance, and how this process changes with age. We will also determine how actin organization and function decline with age, and whether interventions that protect actin and mitochondrial quality control factors from declines with age can affect lifespan control. The proposed studies will extend our understanding of aging in yeast and other polarized cell types including neurons and immune cells that are targets for age-associated disease and senescence.
Mitochondria have emerged as central regulators of aging through their function in energy production, central metabolism and oxidative stress. We find that fitter mitochondria, which have lower oxidative damage, are selectively transferred from mother cells to daughter cells during yeast cell division, and that this process contributes to the fitness and full lifespan of new daughter cells. We have identified mechanisms for inheritance of the fittest mitochondria that are conserved in cells of the nervous and immune systems. Finally, we find that this process is compromised with age and may contribute to age-linked neurodegenerative diseases and immune senescence. We will study the mechanisms for segregation of mitochondria and other aging determinants, and for age-linked declines in these processes.
|Higuchi-Sanabria, Ryo; Swayne, Theresa C; Boldogh, Istvan R et al. (2016) Imaging of the Actin Cytoskeleton and Mitochondria in Fixed Budding Yeast Cells. Methods Mol Biol 1365:63-81|
|Higuchi-Sanabria, Ryo; Garcia, Enrique J; Tomoiaga, Delia et al. (2016) Characterization of Fluorescent Proteins for Three- and Four-Color Live-Cell Imaging in S. cerevisiae. PLoS One 11:e0146120|
|Higuchi-Sanabria, Ryo; Charalel, Joseph K; Viana, Matheus P et al. (2016) Mitochondrial anchorage and fusion contribute to mitochondrial inheritance and quality control in the budding yeast Saccharomyces cerevisiae. Mol Biol Cell 27:776-87|
|Higuchi-Sanabria, Ryo; Swayne, Theresa C; Boldogh, Istvan R et al. (2016) Live-Cell Imaging of Mitochondria and the Actin Cytoskeleton in Budding Yeast. Methods Mol Biol 1365:25-62|
|Pernice, Wolfgang M; Vevea, Jason D; Pon, Liza A (2016) A role for Mfb1p in region-specific anchorage of high-functioning mitochondria and lifespan in Saccharomyces cerevisiae. Nat Commun 7:10595|
|Vevea, Jason D; Garcia, Enrique J; Chan, Robin B et al. (2015) Role for Lipid Droplet Biogenesis and Microlipophagy in Adaptation to Lipid Imbalance in Yeast. Dev Cell 35:584-99|
|Higuchi-Sanabria, Ryo; Pernice, Wolfgang M A; Vevea, Jason D et al. (2014) Role of asymmetric cell division in lifespan control in Saccharomyces cerevisiae. FEMS Yeast Res 14:1133-46|
|Vevea, Jason D; Swayne, Theresa C; Boldogh, Istvan R et al. (2014) Inheritance of the fittest mitochondria in yeast. Trends Cell Biol 24:53-60|
|Wolken, Dana M Alessi; McInnes, Joseph; Pon, Liza A (2014) Aim44p regulates phosphorylation of Hof1p to promote contractile ring closure during cytokinesis in budding yeast. Mol Biol Cell 25:753-62|
|Pon, Liza A (2013) Mitochondrial fission: rings around the organelle. Curr Biol 23:R279-81|
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