Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy: a model of mitochondrial neurodegeneration
Bioenergetics shapes cellular death pathways in Leber's hereditary optic neuropathy: a model of mitochondrial neurodegeneration
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DOI：
10.1016/j.bbabio.2004.05.009
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发表时间：
2004-07-23
影响因子：
4.3
通讯作者：
Solaini, G
中科院分区：
文献类型：
--
作者：
Carelli, V;Rugolo, M;Solaini, G
Leber遗传性视神经病变（LHON）是第一个与线粒体DNA点突变相关的母系遗传性疾病，现在被认为是最普遍的线粒体疾病。病理学特征为视网膜中神经节细胞的选择性丧失，导致中心视力丧失和视神经萎缩，在年轻男性中较常见。LHON的致病性mtDNA点突变影响复合物I，具有降低复合物I底物驱动的ATP合成和慢性增加氧化stress.In这篇综述中，我们首先考虑与携带最常见的LHON突变的胞质杂种细胞中线粒体的质子易位NADH-醌氧化还原酶相关的生化变化。然而，LHON胞质杂种生物能功能障碍在正常条件下（即在葡萄糖培养基中）基本上得到补偿，但未被应激条件（例如在无葡萄糖/半乳糖培养基中生长的胞质杂种）所揭示，这迫使细胞仅依赖于呼吸链进行ATP合成。事实上，本文的第二部分涉及半乳糖培养基中LHON胞质杂种死亡途径的研究。在半乳糖实验的时间过程中，抗氧化酶的平行显着的变化，也揭示了相关的作用所发挥的氧化stress. LHON胞质杂种模型揭示了复杂的相互作用之间的不同水平的生化后果，从复杂的I突变，确定在LHON神经变性，并建议一个未知的作用，生物能量学在塑造细胞死亡途径。(C)2004 Elsevier B. V.保留所有权利。
Leber's hereditary optic neuropathy (LHON) was the first maternally inherited disease to be associated with point mutations in mitochondrial DNA and is now considered the most prevalent mitochondrial disorder. The pathology is characterized by selective loss of ganglion cells in the retina leading to central vision loss and optic atrophy, prevalently in young males. The pathogenic mtDNA point mutations for LHON affect complex I with the double effect of lowering the ATP synthesis driven by complex I substrates and increasing oxidative stress chronically.In this review, we first consider the biochemical changes associated with the proton-translocating NADH-quinone oxidoreductase of mitochondria in cybrid cells carrying the most common LHON mutations. However, the LHON cybrid bioenergetic dysfunction is essentially compensated under normal conditions, i.e. in glucose medium, but is unrevealed by stressful conditions such as growing cybrids in glucose free/galactose medium, which forces cells to rely only on respiratory chain for ATP synthesis. In fact, the second part of this review deals with the investigation of LHON cybrid death pathway in galactose medium. The parallel marked changes in antioxidant enzymes, during the time-course of galactose experiments, also reveal a relevant role played by oxidative stress.The LHON cybrid model sheds light on the complex interplay amongst the different levels of biochemical consequences deriving from complex I mutations in determining neurodegeneration in LHON, and suggests an unsuspected role of bioenergetics in shaping cell death pathways. (C) 2004 Elsevier B.V. All rights reserved.