Department of Pediatrics, Clinical Sciences, Lund University, Lund, Sweden.
Hepatology. 2011 Feb;53(2):437-47. doi: 10.1002/hep.24031. Epub 2010 Dec 28.
Mitochondrial dysfunction is an important cause for neonatal liver disease. Disruption of genes encoding oxidative phosphorylation (OXPHOS) components usually causes embryonic lethality, and thus few disease models are available. We developed a mouse model for GRACILE syndrome, a neonatal mitochondrial disease with liver and kidney involvement, caused by a homozygous BCS1L mutation (232A>G). This gene encodes a chaperone required for incorporation of Rieske iron-sulfur protein (RISP) into complex III of respiratory chain. Homozygous mutant mice after 3 weeks of age developed striking similarities to the human disease: growth failure, hepatic glycogen depletion, steatosis, fibrosis, and cirrhosis, as well as tubulopathy, complex III deficiency, lactacidosis, and short lifespan. BCS1L was decreased in whole liver cells and isolated mitochondria of mutants at all ages. RISP incorporation into complex III was diminished in symptomatic animals; however, in young animals complex III was correctly assembled. Complex III activity in liver, heart, and kidney of symptomatic mutants was decreased to 20%, 40%, and 40% of controls, respectively, as demonstrated with electron flux kinetics through complex III. In high-resolution respirometry, CIII dysfunction resulted in decreased electron transport capacity through the respiratory chain under maximum substrate input. Complex I function, suggested to be dependent on a functional complex III, was, however, unaffected.
We present the first viable model of complex III deficiency mimicking a human mitochondrial disorder. Incorporation of RISP into complex III in young homozygotes suggests another complex III assembly factor during early ontogenesis. The development of symptoms from about 3 weeks of age provides a convenient time window for studying the pathophysiology and treatment of mitochondrial hepatopathy and OXPHOS dysfunction in general.
线粒体功能障碍是新生儿肝病的一个重要原因。编码氧化磷酸化（OXPHOS）组件的基因突变通常导致胚胎致死，因此很少有疾病模型可用。我们开发了一种用于 GRACILE 综合征的小鼠模型，GRACILE 综合征是一种新生儿线粒体疾病，涉及肝脏和肾脏，由同源 BCS1L 突变（232A>G）引起。该基因编码一种伴侣蛋白，对于 Rieske 铁硫蛋白（RISP）整合到呼吸链复合物 III 中是必需的。3 周龄后的纯合突变小鼠表现出与人类疾病非常相似的特征：生长不良、肝糖原耗竭、脂肪变性、纤维化和肝硬化，以及肾小管病、复合物 III 缺乏、乳酸性酸中毒和寿命缩短。在所有年龄段的突变体的全肝细胞和分离的线粒体中，BCS1L 均减少。在有症状的动物中，RISP 整合到复合物 III 中减少；然而，在年轻动物中，复合物 III 被正确组装。在有症状的突变体的肝脏、心脏和肾脏中，复合物 III 的活性分别下降到对照组的 20%、40%和 40%，这是通过复合物 III 电子流动力学来证明的。在高分辨率呼吸测定中，CIII 功能障碍导致最大底物输入下呼吸链的电子传递能力降低。复合物 I 功能，被认为依赖于功能正常的复合物 III，然而，不受影响。
我们提出了第一个模拟人类线粒体疾病的复合物 III 缺陷的可行模型。在年轻的纯合子中，RISP 整合到复合物 III 中表明在早期胚胎发生过程中存在另一种复合物 III 组装因子。大约 3 周龄后出现症状为研究线粒体肝病变和 OXPHOS 功能障碍的病理生理学和治疗提供了一个方便的时间窗口。
