An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast.
An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast.
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作者：
线粒体在衰老过程中起着核心作用。它们被认为是衰老过程的目标，也是衰老过程的贡献者。在大多数真核生物的衰老过程中，线粒体结构和功能的改变是明显的，但人们对这种变化是如何发生的知之甚少。在这里，我们确定了溶酶体样空泡和线粒体在S。酿酒酵母，并表明，线粒体功能障碍，在复制老化的酵母产生改变液泡pH值。我们发现，液泡酸度下降，在早期不对称分裂的母细胞，并表明，防止这种下降抑制线粒体功能障碍，延长寿命。令人惊讶的是，液泡pH的变化并不通过破坏液泡蛋白质降解来限制线粒体功能，而是通过减少液泡腔中pH依赖性氨基酸的储存来限制线粒体功能。我们还发现，热量限制促进寿命延长至少部分通过增加液泡酸度通过保守的营养传感途径。有趣的是，尽管衰老的母细胞中液泡酸性降低，但酸性液泡在新生的子细胞中再生，这与子细胞具有更新的寿命潜力相一致。总的来说，我们的研究结果确定了液泡pH值作为衰老和线粒体功能的关键调节因子，并概述了一种潜在的保守机制，通过这种机制，热量限制延缓了衰老过程。由于液泡的功能在整个进化过程中是高度保守的，我们假设溶酶体pH值可能调节其他真核细胞中线粒体的功能和寿命。
Mitochondria play a central role in ageing. They are considered to be both a target of the ageing process, as well as a contributor to it. Alterations in mitochondrial structure and function are evident during ageing in most eukaryotes, but how this occurs is poorly understood. Here, we identify a functional link between the lysosome-like vacuole and mitochondria in S. cerevisiae, and show that mitochondrial dysfunction in replicatively-aged yeast arises from altered vacuolar pH. We found that vacuolar acidity declines during the early asymmetric divisions of a mother cell, and show that preventing this decline suppresses mitochondrial dysfunction and extends lifespan. Surprisingly, changes in vacuolar pH do not limit mitochondrial function by disrupting vacuolar protein degradation, but rather, by reducing pH-dependent amino acid storage in the vacuolar lumen. We also found that calorie restriction promotes lifespan extension at least in part by increasing vacuolar acidity via conserved nutrient sensing pathways. Interestingly, although vacuolar acidity is reduced in aged mother cells, acidic vacuoles are regenerated in newborn daughters, coinciding with daughter cells having a renewed lifespan potential. Overall, our results identify vacuolar pH as a critical regulator of ageing and mitochondrial function, and outline a potentially conserved mechanism by which calorie restriction delays the ageing process. Because functions of the vacuole are highly conserved throughout evolution, we hypothesize that lysosomal pH may modulate mitochondrial function and lifespan in other eukaryotic cells.
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DOI：
10.1016/j.bbamcr.2008.08.003
发表时间：
2009-04
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Li SC;Kane PM
通讯作者：
Kane PM
影响因子：
4.8
作者：
Nass, R;Cunningham, KW;Rao, R
通讯作者：
Rao, R
影响因子：
4.8
作者：
Russnak, R;Konczal, D;McIntire, SL
通讯作者：
McIntire, SL
影响因子：
7.8
作者：
McFaline-Figueroa JR;Vevea J;Swayne TC;Zhou C;Liu C;Leung G;Boldogh IR;Pon LA
通讯作者：
Pon LA
影响因子：
4.5
作者：
Lindstrom DL;Leverich CK;Henderson KA;Gottschling DE
通讯作者：
Gottschling DE