A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions
A defect in the mitochondrial complex III, but not complex IV, triggers early ROS-dependent damage in defined brain regions
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DOI：
10.1093/hmg/dds350
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发表时间：
2012-12-01
影响因子：
3.5
通讯作者：
Moraes, Carlos T.
中科院分区：
文献类型：
--
作者：
Diaz, Francisca;Garcia, Sofia;Moraes, Carlos T.
我们已经建立了两个神经元特异性的线粒体电子传递链缺陷的小鼠模型，涉及复合物III（CIII）或复合物IV（CIV）的缺陷。这些条件性敲除（cKO）分别通过切除编码Rieske铁硫蛋白（RISP）和COX10的基因而产生。RISP是CIII的催化亚基之一，COX 10是CIV的催化亚基之一Cox1成熟所必需的组装因子。尽管基因缺失、蛋白质丢失和复杂功能障碍的发生率相似，但RISP cKO存活了3.5个月，而COX10 cKO存活了1012个月。RISP cKO发生猝死，行为变化极小。相比之下，COX10 cKO表现出独特的行为表型，在4个月龄时发作，随后是较慢但进行性的神经变性。奇怪的是，梨状皮质和躯体感觉皮质更容易受到CIII缺陷，而扣带回皮质和梨状皮质在较小程度上优先受到CIV缺陷的影响。此外，CIII模型显示出严重的和早期的活性氧损伤，这是直到CIV模型的病理学非常晚期才观察到的特征。这些发现说明了特定的呼吸链缺陷如何具有不同的分子机制，导致不同的病理学，类似于在线粒体疾病患者中观察到的临床异质性。
We have created two neuron-specific mouse models of mitochondrial electron transport chain deficiencies involving defects in complex III (CIII) or complex IV (CIV). These conditional knockouts (cKOs) were created by ablation of the genes coding for the Rieske ironsulfur protein (RISP) and COX10, respectively. RISP is one of the catalytic subunits of CIII and COX10 is an assembly factor indispensable for the maturation of Cox1, one of the catalytic subunits of CIV. Although the rates of gene deletion, protein loss and complex dysfunction were similar, the RISP cKO survived 3.5 months of age, whereas the COX10 cKO survived for 1012 months. The RISP cKO had a sudden death, with minimal behavioral changes. In contrast, the COX10 cKO showed a distinctive behavioral phenotype with onset at 4 months of age followed by a slower but progressive neurodegeneration. Curiously, the piriform and somatosensory cortices were more vulnerable to the CIII defect whereas cingulate cortex and to a less extent piriform cortex were affected preferentially by the CIV defect. In addition, the CIII model showed severe and early reactive oxygen species damage, a feature not observed until very late in the pathology of the CIV model. These findings illustrate how specific respiratory chain defects have distinct molecular mechanisms, leading to distinct pathologies, akin to the clinical heterogeneity observed in patients with mitochondrial diseases.