Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria
Multiple OXPHOS Deficiency in the Liver, Kidney, Heart, and Skeletal Muscle of Patients With Methylmalonic Aciduria and Propionic Aciduria
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DOI：
10.1203/pdr.0b013e3181a7c270
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发表时间：
2009-07-01
影响因子：
3.6
通讯作者：
de Lonlay, Pascale
中科院分区：
文献类型：
--
作者：
de Keyzer, Yves;Valayannopoulos, Vassili;de Lonlay, Pascale
我们研究了 6 名出现各种严重并发症的有机酸尿症 (OA) 患者的组织中的呼吸链 (RC)、三羧酸循环 (TCA) 酶活性和氧化应激，以进一步记录线粒体 OXPHOS 功能障碍在并发症发生中的作用。对两名患有丙酸血症 (PA) 且出现严重心肌病的儿童和四名患有甲基丙二酸尿症 (MMA) 的儿童进行了随访，他们出现了神经系统疾病 (3/4) 和肾功能衰竭 (2/4)。我们测量了患者组织中的 RC 和 TCA 循环酶活性，并评估了体外成纤维细胞的氧化代谢。在 PA 和 MMA 患者的组织中发现了各种 RC 缺陷。调查时，两名测试患者的 TCA 循环酶活性正常，活性氧和解毒系统活性均降低。总之，在六名患有严重并发症的有机酸血症患者的所有研究组织中都发现了线粒体功能障碍。成纤维细胞原代培养物中活性氧的产生和解毒减少。我们的结果进一步支持了继发性呼吸缺陷在这些疾病的晚期多器官并发症的发展中的作用。 （儿科，Res 66：91-95，2009）
We investigated respiratory chain (RC), tricarboxylic acid cycle (TCA) enzyme activities, and oxidative stress in the tissues of six patients with organic aciduria (OA) presenting various severe complications to further document the role of mitochondrial OXPHOS dysfunction in the development of complications. Two children with propionic acidemia (PA), presenting a severe cardiomyopathy, and four with methylmalonic aciduria (MMA), who developed a neurologic disease (3/4) and renal failure (2/4), were followed. We measured RC and TCA cycle enzyme activity in patient tissues and assessed oxidative metabolism in fibroblasts in vitro. Various RC deficiencies were found in tissues of patients with PA and MMA. TCA cycle enzyme activities were normal when investigated and reactive oxygen species were decreased as well as detoxifying systems activities in the two patients tested. In conclusion, mitochondrial dysfunction was found in all investigated tissues of six patients with organic acidemia presenting with severe complications. Reactive oxygen species production and detoxification were decreased in fibroblast primary Cultures. Our results bring further support for a role of secondary respiratory deficiency in the development of late multiorgan complications of these diseases. (Pediatr, Res 66: 91-95, 2009)