Mother-daughter asymmetry of pH underlies aging and rejuvenation in yeast.
Mother-daughter asymmetry of pH underlies aging and rejuvenation in yeast.
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DOI：
10.7554/elife.03504
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发表时间：
2014-09-04
期刊：
影响因子：
7.7
通讯作者：
Gottschling DE
中科院分区：
文献类型：
--
作者：
Henderson KA;Hughes AL;Gottschling DE
酵母的复制老化是不对称的——母细胞老化，而子细胞则恢复活力。在这里，我们确定了母亲和子细胞之间pH值的不对称，这是衰老和年轻化的基础。衰老的母细胞细胞质pH值增加，但子细胞酸性更强。这是由于细胞质pH的主要调节因子，质膜质子atp酶（Pma1）的不对称分布。Pma1在衰老的母细胞中积累，但在新生的子细胞中基本不存在。我们以前发现液泡的酸度在衰老的母细胞中下降并限制了寿命，但子细胞液泡会重新酸化。我们发现Pma1活性通过减少细胞质质子而拮抗母细胞液泡酸性。然而，Pma1固有的不对称性增加了子细胞的细胞质质子可用性，促进了液泡的再酸化和再生。DOI: http://dx.doi.org/10.7554/eLife.03504.001衰老是生命的一部分，但它的生物学基础，特别是衰老细胞如何产生年轻的后代（或后代），还没有明确地建立在任何生物体上。出芽酵母是一种微生物，它是了解人类等更复杂生物体衰老的有价值的模型。出芽的酵母细胞经历一个称为“复制老化”的过程，这意味着每个酵母母细胞在其一生中产生一定数量的子细胞。然而，当衰老的母细胞产生子细胞时，子细胞的年龄被“重置为零”。母细胞如何衰老，它们的子细胞如何恢复活力，这些问题已经被研究了几十年。此前，研究人员发现，随着母细胞的衰老，母细胞的液泡（一种储存重要分子的酸性隔间，这些分子可能会变得有毒）的酸性会降低。另一方面，子细胞具有非常酸性的液泡，这与它们的寿命延长有关。然而，母细胞和子细胞之间液泡酸度差异背后的机制尚不清楚。现在，亨德森等人发现一种蛋白质（称为Pma1）存在于母细胞中，但不存在于新形成的子细胞中，这种蛋白质存在于细胞表面，并将质子泵出细胞。此外，Pma1蛋白也会随着母细胞的衰老而积累。通过将质子泵出细胞，Pma1有效地减少了可用于酸化母细胞液泡的质子数量。然而，因为一开始子细胞没有Pma1，细胞内仍然有大量的质子使液泡酸化。当Henderson等人降低母细胞中Pma1的活性时，整个细胞变得更酸，它们的液泡也变得更酸。相反，经工程改造后含有更多Pma1的子细胞酸性较弱，酸性液泡也比正常细胞少。亨德森等人接着问道，降低Pma1活性以制造酸性更强的细胞是否能延长细胞的寿命，结果发现Pma1活性较低的细胞确实寿命更长。因此，这些发现表明，细胞酸度的不对称——由Pma1蛋白的不平等水平引起——有助于减少母细胞的寿命，并使子细胞恢复活力。因此，亨德森等人已经确定了芽殖酵母细胞老化过程中最早的事件之一。他们的研究结果表明，通常对细胞存活至关重要的一种活性（在这种情况下，是Pma1的活性）的不平衡可能对导致细胞衰老的长期后果。DOI: http://dx.doi.org/10.7554/eLife.03504.002
Replicative aging in yeast is asymmetric–mother cells age but their daughter cells are rejuvenated. Here we identify an asymmetry in pH between mother and daughter cells that underlies aging and rejuvenation. Cytosolic pH increases in aging mother cells, but is more acidic in daughter cells. This is due to the asymmetric distribution of the major regulator of cytosolic pH, the plasma membrane proton ATPase (Pma1). Pma1 accumulates in aging mother cells, but is largely absent from nascent daughter cells. We previously found that acidity of the vacuole declines in aging mother cells and limits lifespan, but that daughter cell vacuoles re-acidify. We find that Pma1 activity antagonizes mother cell vacuole acidity by reducing cytosolic protons. However, the inherent asymmetry of Pma1 increases cytosolic proton availability in daughter cells and facilitates vacuole re-acidification and rejuvenation. DOI: http://dx.doi.org/10.7554/eLife.03504.001 Aging is a part of life—but its biological basis and, in particular, how aged cells give rise to young offspring (or progeny) has not been clearly established for any organism. Budding yeast is a microorganism that is a valuable model to understand aging in more complex organisms like humans. Budding yeast cells undergo a process called ‘replicative aging’, meaning that each yeast mother cell produces a set number of daughter cells in her lifetime. However, when daughter cells arise from an aging mother cell, the daughter's age is ‘reset to zero’. How mother cells age, and how their daughters are rejuvenated, are questions that have been studied for decades. Previously, researchers discovered that a mother cell's vacuole (an acidic compartment that stores important molecules that can become toxic) becomes less acidic as the mother cell ages. Daughter cells, on the other hand, have very acidic vacuoles, which was linked to their renewed lifespans. However, the mechanism behind this difference in the acidity of the vacuole between mother and daughter cells was unknown. Now, Henderson et al. have found that a protein (called Pma1), which is found at the cell surface and pumps protons out of the cell, is present in mother cells but not in their newly-formed daughter cells. Furthermore, the Pma1 protein also accumulates as mother cells age. By pumping protons out of the cell, Pma1 effectively reduces the number of protons available to acidify the vacuole in the mother cell. However, because at first the daughter does not have Pma1, there are still plenty of protons inside the cell to acidify the vacuole. When Henderson et al. reduced the activity of Pma1 in mother cells, the entire cell became more acidic, and so did their vacuoles. Conversely daughter cells engineered to have more Pma1 were less acidic and had less acidic vacuoles than normal. Henderson et al. next asked whether reducing Pma1 activity to create a more acidic cell, could extend the lifespan of cells, and found that indeed cells with less Pma1 activity lived longer. As such, these findings indicate that an asymmetry in the acidity of the cell—caused by unequal levels of the Pma1 protein—contributes to reducing the lifespan of the mother cell and to rejuvenating the daughter cell. Thus Henderson et al. have identified one of the earliest events in the cellular aging process in budding yeast. Their findings suggest that an imbalance in an activity that is normally essential for cell survival (in this case, the activity of Pma1) can have long-term consequences for the cell that lead to aging. DOI: http://dx.doi.org/10.7554/eLife.03504.002