Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca Milano, Italy.
Front Oncol. 2012 Jun 29;2:67. doi: 10.3389/fonc.2012.00067. eCollection 2012.
ACH1 encodes a mitochondrial enzyme of Saccharomyces cerevisiae endowed with CoA-transferase activity. It catalyzes the CoASH transfer from succinyl-CoA to acetate generating acetyl-CoA. It is known that ACH1 inactivation results in growth defects on media containing acetate as a sole carbon and energy source which are particularly severe at low pH. Here, we show that chronological aging ach1Δ cells which accumulate a high amount of extracellular acetic acid display a reduced chronological lifespan. The faster drop of cell survival is completely abrogated by alleviating the acid stress either by a calorie restricted regimen that prevents acetic acid production or by transferring chronologically aging mutant cells to water. Moreover, the short-lived phenotype of ach1Δ cells is accompanied by reactive oxygen species accumulation, severe mitochondrial damage, and an early insurgence of apoptosis. A similar pattern of endogenous severe oxidative stress is observed when ach1Δ cells are cultured using acetic acid as a carbon source under acidic conditions. On the whole, our data provide further evidence of the role of acetic acid as cell-extrinsic mediator of cell death during chronological aging and highlight a primary role of Ach1 enzymatic activity in acetic acid detoxification which is important for mitochondrial functionality.
ACH1 编码酿酒酵母中的一种线粒体酶，具有 CoA 转移酶活性。它催化从琥珀酰辅酶 A 到乙酸的 CoASH 转移，生成乙酰辅酶 A。已知 ACH1 失活会导致在含有乙酸作为唯一碳源和能源的培养基上生长缺陷，在低 pH 值时尤为严重。在这里，我们表明，积累大量细胞外乙酸的时序老化 ach1Δ 细胞显示出较短的时序寿命。通过限制卡路里的饮食方案来预防乙酸的产生，或者将时序老化的突变细胞转移到水中，从而减轻酸应激，可以完全消除细胞存活率下降的更快趋势。此外，ach1Δ 细胞的短命表型伴随着活性氧的积累、严重的线粒体损伤和早期细胞凋亡的发生。当 ach1Δ 细胞在酸性条件下使用乙酸作为碳源进行培养时，也观察到类似的内源性严重氧化应激模式。总的来说，我们的数据进一步证明了乙酸作为细胞外细胞死亡介质在时序老化过程中的作用，并强调了 Ach1 酶活性在乙酸解毒中的主要作用，这对于线粒体功能很重要。
