Mechanisms of retinal ganglion specific-cell death in Leber hereditary optic neuropathy.
Mechanisms of retinal ganglion specific-cell death in Leber hereditary optic neuropathy.
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发表时间：
2007
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通讯作者：
L. Levin
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作者：
L. Levin
目的莱伯遗传性视神经病 (LHON) 是由存在于所有细胞中的线粒体 DNA (mtDNA) 点突变引起的，但仅在视网膜神经节细胞 (RGC) 中表现出来。鉴于 RGC 在轴突切除后使用超氧化物进行细胞内信号传导，并且 LHON 突变会增加非 RGC 传输软骨细胞中的超氧化物水平，我假设 RGC 调节超氧化物水平的方式与其他神经元细胞不同。方法测量从 RGC-5 细胞系、大鼠脑或神经母细胞瘤 SK-N-AS 细胞分离的线粒体中的超氧化物产量，并将其与线粒体电子传递链 (METC) 复合物的水平相关联。结果 当使用复合物 I 底物时，脑线粒体中超氧化物产生的速率是 RGC-5 细胞中超氧化物产生速率的 5 倍以上。鱼藤酮显着增加了大脑中超氧化物产生的速率，但不增加 RGC-5 线粒体中的超氧化物产生速率。大脑和 RGC-5 线粒体中琥珀酸依赖性超氧化物的产生相似，但仅在脑细胞中被复合物 III 抑制剂抗霉素 A 增加。神经母细胞瘤线粒体表现出与脑细胞相似的超氧化物生成率。较低的超氧化物生成率可能反映了较低水平的 METC 成分。结论 这些结果表明，RGC-5 线粒体产生超氧化物的速率明显低于脑线粒体。更严格地调节 RGC 中的超氧化物水平将防止异常的细胞凋亡信号传导。 LHON mtDNA 突变可能会干扰超氧化物调节，可能导致异常的 RGC 死亡和随后的视神经病变。
PURPOSE Leber hereditary optic neuropathy (LHON) results from point mutations in mitochondrial DNA (mtDNA) present in all cells but is only manifested in retinal ganglion cells (RGCs). Given that RGCs use superoxide for intracellular signaling after axotomy, and that LHON mutations increase superoxide levels in non-RGC transmitochondrial cybrids, I hypothesized that RGCs regulate superoxide levels differently than other neuronal cells. METHODS Superoxide production in mitochondria isolated from the RGC-5 cell line, rat brain, or neuroblastoma SK-N-AS cells was measured and correlated with levels of mitochondrial electron transport chain (METC) complexes. RESULTS The rate of superoxide production in brain mitochondria was more than 5 times the rate in RGC-5 cells when complex I substrates were used. Rotenone significantly increased the rate of superoxide production in brain but not RGC-5 mitochondria. Succinate-dependent superoxide production was similar in brain and RGC-5 mitochondria, but was increased by the complex III inhibitor antimycin A only in brain cells. Neuroblastoma mitochondria demonstrated similar superoxide generation rates as brain cells. Lower rates of superoxide production probably reflected lower levels of METC components. CONCLUSIONS These results demonstrate that RGC-5 mitochondria produce superoxide at significantly lower rates than brain mitochondria. Tighter regulation of superoxide levels in RGCs would prevent aberrant apoptosis signaling. LHON mtDNA mutations may interfere with superoxide regulation, possibly leading to aberrant RGC death and consequent optic neuropathy.