Long Jiangang, Liu Changsheng, Sun Lijuan, Gao Hongxiang, Liu Jiankang
Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697-4540, USA.
Neurochem Res. 2009 Apr;34(4):786-94. doi: 10.1007/s11064-008-9882-7. Epub 2008 Nov 21.
Malondialdehyde (MDA) is a product of oxidative damage to lipids, amino acids and DNA, and accumulates with aging and diseases. MDA can possibly react with amines so as to modify proteins and inactivate enzymes; it can also modify nucleosides so as to cause mutagenicity. Brain mitochondrial dysfunction is a major contributor to aging and neurodegenerative diseases. We hypothesize that MDA accumulated during aging targets mitochondrial enzymes so as to cause further mitochondrial dysfunction and additional contributions to aging and neurodegeneration. Herein, we investigated the neuronal mitochondrial toxic effects of MDA on mitochondrial respiration and activities of enzymes (mitochondrial complexes I-V, alpha-ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase (PDH)), in isolated rat brain mitochondria. MDA depressed mitochondrial membrane potential, and also showed a dose-dependent inhibition of mitochondrial complex I- and complex II-linked respiration. Complex I and II, and PDH activities were depressed by MDA at >or=0.2 micromol/mg; KGDH and complex V were inhibited by >or=0.4 and >or=1.6 micromol MDA/mg, respectively. However, MDA did not have any toxic effects on complex III and IV activities over the range 0-2 micromol/mg. MDA significantly elevated mitochondrial reactive oxygen species (ROS) and protein carbonyls at 0.2 and 0.002 micromol/mg, respectively. As for the antioxidant defense system, a high dose of MDA slightly decreased mitochondrial GSH and superoxide dismutase. These results demonstrate that MDA causes neuronal mitochondrial dysfunction by directly promoting generation of ROS and modifying mitochondrial proteins. The results suggest that MDA-induced neuronal mitochondrial toxicity may be an important contributing factor to brain aging and neurodegenerative diseases.
丙二醛（MDA）是脂质、氨基酸和DNA氧化损伤的产物，会随着衰老和疾病而积累。MDA可能与胺发生反应，从而修饰蛋白质并使酶失活；它还可以修饰核苷，从而导致致突变性。脑线粒体功能障碍是衰老和神经退行性疾病的主要原因。我们假设衰老过程中积累的MDA靶向线粒体酶，从而导致进一步的线粒体功能障碍，并对衰老和神经退行性变产生额外影响。在此，我们研究了MDA对分离的大鼠脑线粒体中细胞呼吸以及酶（线粒体复合物I-V、α-酮戊二酸脱氢酶（KGDH）和丙酮酸脱氢酶（PDH））活性的神经元线粒体毒性作用。MDA降低了线粒体膜电位，并且还对线粒体复合物I和复合物II相关的呼吸表现出剂量依赖性抑制。当MDA浓度≥0.2 μmol/mg时，复合物I和II以及PDH的活性受到抑制；KGDH和复合物V分别在MDA浓度≥0.4 μmol/mg和≥1.6 μmol/mg时受到抑制。然而，在0-2 μmol/mg范围内，MDA对复合物III和IV的活性没有任何毒性作用。MDA分别在浓度为0.2 μmol/mg和0.002 μmol/mg时显著提高了线粒体活性氧（ROS）和蛋白质羰基水平。至于抗氧化防御系统，高剂量的MDA略微降低了线粒体谷胱甘肽（GSH）和超氧化物歧化酶水平。这些结果表明，MDA通过直接促进ROS的产生和修饰线粒体蛋白而导致神经元线粒体功能障碍。结果表明，MDA诱导的神经元线粒体毒性可能是脑衰老和神经退行性疾病的一个重要促成因素。
