TY - JOUR
T1 - Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing
AU - Eldakak, Amr
AU - Rancati, Giulia
AU - Rubinstein, Boris
AU - Paul, Parama
AU - Conaway, Veronica
AU - Li, Rong
N1 - Funding Information:
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.
PY - 2010/8
Y1 - 2010/8
N2 - Cellular ageing is known to correlate with the accumulation of many harmful agents, 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.
AB - Cellular ageing is known to correlate with the accumulation of many harmful agents, 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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U2 - 10.1038/ncb2085
DO - 10.1038/ncb2085
M3 - Article
C2 - 20657593
AN - SCOPUS:77955175082
SN - 1465-7392
VL - 12
SP - 799
EP - 805
JO - Nature cell biology
JF - Nature cell biology
IS - 8
ER -