Mammalian sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
Mammalian sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
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DOI：
10.1128/mcb.01636-07
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发表时间：
2007-12-01
影响因子：
5.3
通讯作者：
Schwer, Bjoern
中科院分区：
文献类型：
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作者：
Lombard, David B.;Alt, Frederick W.;Schwer, Bjoern
酿酒酵母Sir2蛋白的同源物sirtuins在许多生物中促进长寿。对sirtuin SIRT3的研究迄今仅限于细胞培养系统。在这里，我们研究SIRT3在体内的定位和功能。我们表明，内源性小鼠SIRT3是一种可溶性线粒体蛋白。为了解决SIRT3在能量代谢调节中的功能和相关性，我们产生并表型表征了SIRT3敲除小鼠。SIRT3缺陷的动物表现出惊人的线粒体蛋白的超乙酰化，表明SIRT3是一个主要的线粒体脱乙酰酶。相比之下，在缺乏另外两种线粒体sirtuins，SIRT4和SIRT5的小鼠中没有检测到线粒体超乙酰化。令人惊讶的是，尽管有这种生化表型，SIRT3缺陷型小鼠在基础条件下代谢不显著，并显示正常的适应性产热，这一过程先前被认为涉及SIRT3。总的来说，我们的研究结果扩展了最近发现的线粒体蛋白的赖氨酸乙酰化，并证明SIRT3已经进化到控制这个细胞器中的可逆赖氨酸乙酰化。
Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.