大GTPase家族蛋白在线粒体病中的作用机制初探

Mitochondrial disorder results in defects of respiratory chain complex mainly due to the mtDNA mutations, causing the damage of organ or tissue which require energy. In previous study, we find that peripheral lymphocytes exhibits the abnormality of mitochondrial fission and fusion in these patients.It is clear that the large GTPase proteins are closely related to mitochondrial fission and fusion. In the present study,we first explore whether the protein of GTPase family is a responsible protein for mitochondrial fission and fusion in m.A3243G fibroblast cells.Second,we set up the cybrid cells that cybrided with 143Bρ0 cells and m.A3243G fibroblast cells, and compare the large GTPase family proteins with the control 143B cells.We try to confirm there is no relationship between m.A3243G mutation and mitochondrial dynamic.Finaly,we interfere the expression of the responsible protein by using siRNA and transfection techeniques in the 143B cybrid cells, and define that the protein is involved in the mitochondrial functions,including respiratory chain complex activity and mitochondrial membrane electricity. This study provides strong evidence that large GTPase family protein participates in mitochondrial fusion and fission.Our results could demonstrate novel clue for the pathogenesis of mitochondrial disorder..

线粒体病是一种线粒体代谢障碍性疾病。我们前期发现，线粒体病患者外周血淋巴细胞存在线粒体分裂融合异常，而该现象与大GTPase家族蛋白密切相关。本研究从该现象出发，构建线粒体病最常见的m.A3243G成纤维细胞，探索大GTPase家族中导致出现线粒体融合分裂现象相关的责任蛋白。建立143Bρ0细胞和m.A3243G突变成纤维细胞的杂合细胞，与143B细胞比较大GTPase家族蛋白表达差异，明确m.A3243G突变与线粒体融合分裂异常无关。通过对143B突变杂合细胞进行RNA干扰和过表达大GTPase家族责任蛋白，证实大GTPase家族蛋白在杂合细胞中导致了线粒体融合分裂异常，并引起相关线粒体功能障碍及线粒体基因再分配异常。由此，我们认为在线粒体病发病机制中，除了线粒体基因突变外，大GTPase家族蛋白也起到了重要作用。本研究将为线粒体病发病原因提出新的思路。

线粒体病是一种线粒体代谢障碍性疾病。我们前期发现，线粒体病患者外周血淋巴细胞存在线粒体分裂融合异常，而该现象与大GTPase家族蛋白密切相关。本研究从该现象出发，构建线粒体病最常见的m.A3243G成纤维细胞，建立143Bρ0细胞和m.A3243G突变成纤维细胞的杂合细胞，与143B细胞比较大GTPase家族蛋白表达差异，发现线粒体分裂蛋白Fis1在不同组别中存在差异。通过对143B突变杂合细胞进行RNA干扰和过表达Fis1蛋白，证实m.A3243G突变与线粒体融合分裂异常无关。Fis1蛋白在杂合细胞中导致了线粒体融合分裂异常，并引起相关线粒体功能障碍及线粒体基因再分配异常。由此，我们认为在线粒体病发病机制中，除了线粒体基因突变外，Fis1蛋白也起到了重要作用。本研究将为线粒体病发病原因提出新的思路。