【译文】线粒体在衰老中发挥重要作用。它们被认为是衰老过程的靶点,并是衰老的促进因子。线粒体结构和功能的改变在多数真核生物衰老期间很明显,但这是如何发生的,目前尚不清楚。 本研究在酿酒酵母中鉴定了溶酶体样液泡和线粒体之间的功能联系,并表明老化的酵母中线粒体功能紊乱是由液泡pH变化引起的。我们发现在母细胞早期不对称分裂期间液泡酸度降低,而阻断这种酸度降低会抑制线粒体功能紊乱并延长生命。令人惊奇的是,液泡pH的变化并不是通过干扰液泡蛋白降解,而是通过减少液泡腔内pH依赖的氨基酸存储而限制线粒体功能的。我们还发现热量限制可以促进生命延长,而这至少是部分依赖通过保守的养分传感通路增加液泡酸度。 有趣的是,尽管液泡酸度在衰老的母细胞中减少,但酸性的液泡在新生细胞中再生了,这与子细胞具有更新寿命潜能相一致。总之,我们的结果鉴定了液泡pH是衰老和线粒体功能的重要调控因子,并鉴定出一种潜在地保守机制,其中热量限制延迟了衰老过程。因为液泡的功能在进化中高度保守,我们提出溶酶体pH可能能调控其他真核细胞中线粒体和寿命。


[Title]: An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast

[Authors]:Adam L. Hughes1 & Daniel E. Gottschling1

[Abstract]Mitochondria have a central role in ageing. They are considered to be both a target of the ageing process and 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 Saccharomyces 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 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 the functions of the vacuole are highly conserved throughout evolution, we propose that lysosomal pH may modulate mitochondrial function and lifespan in other eukaryotic cells.



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