Systematic analysis of asymmetric partitioning of yeast proteome between mother and daughter cells reveals “aging factors” and mechanism of lifespan asymmetry

Abstract

Budding yeast divides asymmetrically, giving rise to a mother cell that progressively ages and a daughter cell with full lifespan. It is generally assumed that mother cells retain damaged, lifespan limiting materials ("aging factors") through asymmetric division. However, the identity of these aging factors and the mechanisms through which they limit lifespan remain poorly understood. Using a flow cytometry-based, high-throughput approach, we quantified the asymmetric partitioning of the yeast proteome between mother and daughter cells during cell division, discovering 74 mother-enriched and 60 daughterenriched proteins. While daughter-enriched proteins are biased toward those needed for bud construction and genome maintenance, mother-enriched proteins are biased towards those localized in the plasma membrane and vacuole. Deletion of 23 of the 74 motherenriched proteins leads to lifespan extension, a fraction that is about six times that of the genes picked randomly from the genome. Among these lifespan-extending genes, three are involved in endosomal sorting/endosome to vacuole transport, and three are nitrogen source transporters. Tracking the dynamic expression of specific mother-enriched proteins revealed that their concentration steadily increases in the mother cells as they age, but is kept relatively low in the daughter cells via asymmetric distribution. Our results suggest that some mother-enriched proteins may increase to a concentration that becomes deleterious and lifespan-limiting in aged cells, possibly by upsetting homeostasis or leading to aberrant signaling. Our study provides a comprehensive resource for analyzing asymmetric cell division and aging in yeast, which should also be valuable for understanding similar phenomena in other organisms.aging | asymmetric cell division | proteome C ellular aging and asymmetric cell division are intimately linked. In budding yeast, asymmetric cell division yields a mother cell and a daughter cell that are easily distinguishable under the microscope. Tracking the fate of the mother lineage led to the discovery that individual mother cells have a finite replicative lifespan, defined by the number of daughters a mother cell produced before senescence (1). It is known that although the mother cell ages with each division, their daughters retain the same full lifespan independent of the age of the mother at least until the last few mother cell divisions (2, 3). Thus, the asymmetry in cell division leads to asymmetry of aging.Even in single-celled organisms in which cell division is seemingly morphologically symmetric, such as fission yeast or Escherichia coli, asymmetric partitioning of cellular contents can still occur and have a differential impact on the aging/death fate of the two offspring (4-8). Asymmetric cell division is also a general phenomenon in mammalian cells (e.g., during development or in mitotically active tissues), where cell division typically leads to two cells with distinct fates, often with different replicative potential. It has been argued...

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Microfluidic technologies for yeast replicative lifespan studies

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