Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase
Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase
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DOI：
10.1172/jci118798
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发表时间：
1996-07-15
影响因子：
15.9
通讯作者：
Robinson, BH
中科院分区：
文献类型：
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作者：
Pitkanen, S;Robinson, BH
从健康个体（对照）和线粒体呼吸链复合体I（NADH-CoQ还原酶）缺乏的一组患者的皮肤成纤维细胞培养物中分离线粒体。复合物I缺乏的患者包括致命性婴儿乳酸性酸中毒（FILA）、白内障心肌病（CC）、肝小管病（HT）、利氏病（LD）、白内障和发育迟缓（CD）以及新生儿期乳酸血症（MS）。在添加NADH的情况下，利用荧光探针lucigenin与分离的成纤维细胞线粒体膜测量超氧自由基的产生。超氧化物生成速率在CD条件下最高，并且在CD顺序上的下降幅度远远大于MS条件下> LD >对照> HT > FILA = CC。然而，ELISA技术检测到的mn -超氧化物歧化酶（MnSOD）的数量在CC和FILA条件下最高，而在CD条件下最低。我们假设，当配合物I活性受损时，氧自由基的产生会增加。然而，观察到的超氧化物产生速率是由MnSOD的变异诱导调节的，它降低了速率，有时低于对照成纤维细胞线粒体的速率。反过来，我们表明，MnSOD的变异诱导最有可能是细胞氧化还原状态变化的功能，而不是复合物I缺陷本身的结果。
Mitochondria were isolated from skin fibroblast cultures derived from healthy individuals (controls) and from a group patients with complex I(NADH-CoQ reductase) deficiency of the mitochondrial respiratory chain. The complex I deficient patients included those with fatal infantile lactic acidosis (FILA), cardiomyopathy with cataracts (CC), hepatopathy with tubulopathy (HT), Leigh's disease (LD), cataracts and developmental delay (CD), and lactic acidemia in the neonatal period followed by mild symptoms (MS). Production of superoxide radicals, on addition of NADH, were measured using the luminometric probe lucigenin with isolated fibroblast mitochondrial membranes. Superoxide production rates were highest with CD and decreased in the order CD much greater than MS > LD > control > HT > FILA = CC. The quantity of Mn-superoxide dismutase (MnSOD), as measured by ELISA techniques, however, was highest in CC and FILA and lowest in CD. Plots of MnSOD quantity versus superoxide production showed an inverse relationship for most conditions with complex I deficiency. We hypothesize that oxygen radical production is increased when complex I activity is compromised. However, the observed superoxide production rates are modulated by the variant induction of MnSOD which decreases the rates, sometimes below those seen in control fibroblast mitochondria. In turn, we show that the variant induction of MnSOD is most likely a function of the change in the redox state of the cell experienced rather than a result of the complex I defect per se.