Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA
Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA
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DOI：
10.1093/hmg/10.11.1221
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发表时间：
2001-05-15
影响因子：
3.5
通讯作者：
Rustin, P
中科院分区：
文献类型：
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作者：
Geromel, V;Kadhom, N;Rustin, P
研究了神经源性视网膜色素共济失调(NARP)线粒体ATPase 6基因突变对皮肤成纤维细胞氧化应激的影响。作为超氧化物产生过剩的一个指标，在这些含有90%突变线粒体DNA的成纤维细胞中观察到超氧化物歧化酶(SOD)活性的巨大诱导，以高SOD活性表示的氧化应激与细胞死亡增加有关。在富糖培养液中，细胞凋亡是复合体V缺乏的主要细胞死亡过程。抗氧化剂自旋陷阱分子全氟三苯基硝酮成功地拯救了复杂的V缺陷型成纤维细胞，该细胞具有较高的超氧化物歧化酶诱导力，且所有研究的凋亡标志物染色均为阳性。这证明，与NARP突变引发的ATPase缺陷相关的超氧化物产生可能足以推翻细胞的抗氧化防御，并导致细胞承诺死亡。超氧化物和/或其衍生物可能参与特定呼吸链疾病的发病机制，使其成为有希望的治疗靶点。
The oxidative stress resulting from the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the mitochondrial ATPase 6 gene was investigated in cultured skin fibroblasts from two patients presenting an isolated complex V deficiency. Taken as an index for superoxide overproduction, a huge induction of the superoxide dismutase (SOD) activity was observed in these fibroblasts harboring > 90% of mutant mitochondrial DNA, The oxidative stress denoted by the high SOD activity was associated with increased cell death. In glucose-rich medium, apoptosis appeared as the main cell death process associated with complex V deficiency. Complex V-deficient fibroblasts, which showed a high SOD induction and stained positive for all studied apoptosis markers, were successfully rescued by perfluoro-tris-phenyl nitrone, an antioxidant spin-trap molecule. This established that the superoxide production associated with the ATPase deficiency triggered by the NARP mutation could be sufficient to override cell antioxidant defenses and to result in cell commitment to die. The potential participation of superoxides and/or their derivatives in the pathogenic mechanism of specific respiratory chain disorders makes them a promising target for therapy.