Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria.
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DOI：
10.1021/bi901627u
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发表时间：
2010-01-19
期刊：
影响因子：
2.9
通讯作者：
Koc, Emine C.
中科院分区：
文献类型：
--
作者：
Cimen, Huseyin;Han, Min-Joon;Yang, Yongjie;Tong, Qiang;Koc, Hasan;Koc, Emine C.
SIRT3是NAD+依赖性脱乙酰酶sirtuin家族的成员，被鉴定为位于哺乳动物线粒体中的主要线粒体脱乙酰酶之一，负责多种代谢酶和氧化磷酸化组分的脱乙酰化。SIRT3对蛋白质脱乙酰化的调节对于线粒体代谢、细胞存活和寿命是重要的。在这项研究中，我们确定了一个复合物II亚基，琥珀酸脱氢酶黄素蛋白（SdhA）亚基，作为一种新的SIRT3底物在SIRT3基因敲除小鼠。几个乙酰化的赖氨酸残基被映射的串联质谱，我们确定了SIRT3基因敲除小鼠中的复合物II活性的乙酰化的作用。与SIRT3依赖的复合物I的活化一致，我们观察到SdhA亚基的脱乙酰化增加了野生型小鼠中的复合物II活性。此外，我们用烟酰胺和山奈酚处理K562细胞系，分别抑制SIRT3的脱乙酰酶活性和刺激SIRT3的表达。与对照和烟酰胺处理的细胞相比，SIRT3表达的刺激降低了山奈酚处理的细胞中SdhA亚基的乙酰化，并增加了复合物II的活性。从猪和鸡的SdhA晶体结构中的乙酰化残基的评估表明，SdhA的亲水性表面的乙酰化可以控制底物进入蛋白质的活性位点，并调节酶的活性。我们的研究结果构成了第一个证据的调节复合物II活性的可逆乙酰化的SdhA亚基作为一种新的底物的NAD+依赖性脱乙酰酶，SIRT3。
A member of the sirtuin family of NAD+-dependent deacetylases, SIRT3 is identified as one of major mitochondrial deacetylase located in mammalian mitochondria responsible for deacetylation of several metabolic enzymes and components of oxidative phosphorylation. Regulation of protein deacetylation by SIRT3 is important for mitochondrial metabolism, cell survival and longevity. In this study, we identified one of the Complex II subunits, succinate dehydrogenase flavoprotein (SdhA) subunit, as a novel SIRT3 substrate in SIRT3 knock-out mice. Several acetylated Lys residues were mapped by tandem mass spectrometry and we determined the role of acetylation on Complex II activity in SIRT3 knock-out mice. In agreement with SIRT3 dependent activation of Complex I, we observed that deacetylation of SdhA subunit increased the Complex II activity in wild type mice. In addition, we treated K562 cell lines with nicotinamide and kaempferol to inhibit deacetylase activity of SIRT3 and stimulate SIRT3 expression, respectively. Stimulation of SIRT3 expression decreased acetylation of the SdhA subunit and increased Complex II activity in kaempherol-treated cells compared to control and nicotinamide treated cells. Evaluation of acetylated residues in SdhA crystal structure from porcine and chicken suggest that acetylation of the hydrophilic surface of SdhA may control the substrate entry to the active site of the protein and regulate the enzyme activity. Our findings constitute the first evidence for the regulation of Complex II activity by the reversible acetylation of the SdhA subunit as a novel substrate of the NAD+- dependent deacetylase, SIRT3.
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影响因子：
3.9
作者：
Rose, G;Dato, S;De Benedictis, G
通讯作者：
De Benedictis, G
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
4
作者：
Marfe, Gabriella;Tafani, Marco;Russo, Matteo Antonio
通讯作者：
Russo, Matteo Antonio
影响因子：
8
作者：
Jin, Lei;Galonek, Heidi;Westphal, Christoph H.
通讯作者：
Westphal, Christoph H.
影响因子：
4.1
作者：
JACKSON, PJ;HARRIS, DA
通讯作者：
HARRIS, DA