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Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing

Nature Cell Biology volume 12, pages 799–805 (2010)Cite this article

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Abstract

Cellular ageing is known to correlate with the accumulation of many harmful agents1, but it is unclear whether ageing can also result from the deterioration of components that are beneficial to the cell, but have a low rate of renewal. Here, we report a group of plasma membrane-associated transporters in yeast, belonging to the multidrug resistance (MDR) protein families, that may represent the latter type of ageing determinants. During the division of a yeast cell, newly synthesized transporter proteins are deposited mostly into the growing bud, whereas previously synthesized MDR proteins remain tightly associated with the mother cortex. Thus, the new and old pools of membrane-bound MDR proteins are spatially segregated during yeast asymmetric cell division, with the older pool stably inherited by the ageing mother. A model based on the observed dynamics of MDR protein inheritance and turnover predicted a decline in MDR activity as the mother cell advances in replicative age. As MDR proteins have crucial roles in cellular metabolism, detoxification and stress response, their collective decline may lead to fitness loss at an advanced age. Supporting this hypothesis, mutants lacking certain MDR genes exhibited a reduced replicative lifespan (RLS), whereas introduction of only one extra copy of these MDR genes extended RLS.

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Figure 1: A group of MDR transporter proteins are asymmetrically localized to the mother cortex in a cell-cycle-regulated manner.
Figure 2: The timing of TPO1 expression during the cell cycle is critical to the observed localization patterns.
Figure 3: Stable inheritance, protein abundance and activity changes of Tpo1 during RLS.
Figure 4: Levels of different MDR transporters affect the replicative lifespan.

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Acknowledgements

We thank C. Zhou for assistance on RLS experiments; C. Seidel and B. Fleharty for help on RNA purification and quantitative RT–PCR; R. Zhu, K. Wagner and J. Haug for assistamce with cell-sorting experiments and B. Slaughter, N. Pavelka and S. Xia for technical advice and critical comments. This research is supported by the National Institutes of Health, grant R01GM057063 to R.L. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

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Authors and Affiliations

  1. Stowers Institute for Medical Research, 1000 East 50 Street, Kansas City, MO 64110, USA.,

    Amr Eldakak, Giulia Rancati, Boris Rubinstein, Parama Paul, Veronica Conaway & Rong Li

  2. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.,

    Rong Li

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  1. Amr Eldakak
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Contributions

A.E. performed all of the experiments and prepared the manuscript figures and draft. G.R. contributed to MDR protein quantification and RLS measurements. B.R. constructed the mathematical model for MDR dynamics during RLS. P.P. and V.C. provided technical assistance for various experiments. R.L. conceived and supervised the project and revised the manuscript.

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Correspondence to Rong Li.

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Eldakak, A., Rancati, G., Rubinstein, B. et al. Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing. Nat Cell Biol 12, 799–805 (2010). https://doi.org/10.1038/ncb2085

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