Pocernich Chava B, Butterfield D Allan
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Neurotox Res. 2003;5(7):515-20. doi: 10.1007/BF03033161.
In Alzheimer's disease (AD) brain increased lipid peroxidation and decreased energy utilization are found. Mitochondria membranes contain a significant amount of arachidonic and linoleic acids, precursors of lipid peroxidation products, 4-hydroxynonenal (HNE) and 2-propen-1-al (acrolein), that are extremely reactive. Both alkenals are increased in AD brain. In this study, we examined the effects of nanomolar levels of acrolein on the activities of pyruvate dehydrogenase (PDH) and Alpha-ketoglutarate dehydrogenase (KGDH), both reduced nicotinamide adenine dinucleotide (NADH)-linked mitochondrial enzymes. Acrolein decreased PDH and KGDH activities significantly in a dose-dependent manner. Using high performance liquid chromatography coupled to mass spectrometry (HPLC-MS), acrolein was found to bind lipoic acid, a component in both the PDH and KGDH complexes, most likely explaining the loss of enzyme activity. Acrolein also interacted with oxidized nicotinamide adenine dinucleotide (NAD(+)) in such a way as to decrease the production of NADH. Acrolein, which is increased in AD brain, may be partially responsible for the dysfunction of mitochondria and loss of energy found in AD brain by inhibition of PDH and KGDH activities, potentially contributing to the neurodegeneration in this disorder.
在阿尔茨海默病（AD）患者的大脑中，发现脂质过氧化增加而能量利用减少。线粒体膜含有大量花生四烯酸和亚油酸，它们是脂质过氧化产物4-羟基壬烯醛（HNE）和2-丙烯醛（丙烯醛）的前体，这些产物具有极强的反应性。这两种烯醛在AD患者的大脑中均有增加。在本研究中，我们检测了纳摩尔水平的丙烯醛对丙酮酸脱氢酶（PDH）和α-酮戊二酸脱氢酶（KGDH）活性的影响，这两种酶都是与还原型烟酰胺腺嘌呤二核苷酸（NADH）相关的线粒体酶。丙烯醛以剂量依赖的方式显著降低了PDH和KGDH的活性。使用高效液相色谱-质谱联用（HPLC-MS）技术，发现丙烯醛与硫辛酸结合，硫辛酸是PDH和KGDH复合物中的一种成分，这很可能解释了酶活性的丧失。丙烯醛还与氧化型烟酰胺腺嘌呤二核苷酸（NAD(+)）相互作用，从而减少了NADH的产生。在AD患者大脑中增加的丙烯醛，可能通过抑制PDH和KGDH的活性，部分导致了AD大脑中线粒体功能障碍和能量丧失，这可能是该疾病神经退行性变的原因之一。
