Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species
Inactivation of Pyruvate Dehydrogenase Kinase 2 by Mitochondrial Reactive Oxygen Species
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DOI：
10.1074/jbc.m112.400002
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发表时间：
2012-10-12
影响因子：
4.8
通讯作者：
James, Andrew M.
中科院分区：
文献类型：
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作者：
Hurd, Thomas R.;Collins, Yvonne;James, Andrew M.
活性氧是线粒体呼吸的副产物，因此是线粒体功能的潜在调节剂。丙酮酸脱氢酶激酶2（PDHK 2）抑制丙酮酸脱氢酶复合物，从而调节碳水化合物进入三羧酸（TCA）循环。在这里，我们表明，PDHK 2活性被呼吸链产生的低水平过氧化氢（H2 O2）抑制。这通过PDHK 2上半胱氨酸残基45和392的可逆氧化发生，并导致丙酮酸脱氢酶复合物活性增加。H2 O2来源于超氧化物（O-2（（中心点）在酒吧）），我们表明，抑制PDHK 2的条件也抑制TCA循环酶，乌头酸酶。这些发现表明，在高线粒体O-2（（中心点）在酒吧）生产的条件下，如可能发生在营养过剩和低ATP需求下，O-2（和H2 O2）的增加可能提供反馈信号，以调节线粒体代谢。
Reactive oxygen species are byproducts of mitochondrial respiration and thus potential regulators of mitochondrial function. Pyruvate dehydrogenase kinase 2 (PDHK2) inhibits the pyruvate dehydrogenase complex, thereby regulating entry of carbohydrates into the tricarboxylic acid (TCA) cycle. Here we show that PDHK2 activity is inhibited by low levels of hydrogen peroxide (H2O2) generated by the respiratory chain. This occurs via reversible oxidation of cysteine residues 45 and 392 on PDHK2 and results in increased pyruvate dehydrogenase complex activity. H2O2 derives from superoxide (O-2((center dot) over bar)), and we show that conditions that inhibit PDHK2 also inactivate the TCA cycle enzyme, aconitase. These findings suggest that under conditions of high mitochondrial O-2((center dot) over bar) production, such as may occur under nutrient excess and low ATP demand, the increase in O-2( and H2O2 may provide feedback signals to modulate mitochondrial metabolism.