Charcot-Marie-Tooth-related Gene GDAP1 Complements Cell Cycle Delay at G2/M Phase in Saccharomyces cerevisiae fis1 Gene-defective Cells
Charcot-Marie-Tooth-related Gene GDAP1 Complements Cell Cycle Delay at G2/M Phase in Saccharomyces cerevisiae fis1 Gene-defective Cells
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DOI：
10.1074/jbc.m111.260042
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发表时间：
2011-10-21
影响因子：
4.8
通讯作者：
Palau, Francesc
中科院分区：
文献类型：
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作者：
Estela, Anna;Pla-Martin, David;Palau, Francesc
GDAP 1基因突变导致Charcot-Marie-Tooth CMT 4A、ARCMT 2K和CMT 2K变体。GDAP 1是一种线粒体外膜蛋白，与线粒体网络动力学的裂变途径有关。由于线粒体动力学是一个保守的过程，我们推断，在参与线粒体分裂或融合的基因缺陷的酿酒酵母菌株中表达GDAP 1可以增加我们对GDAP 1功能的了解。我们发现Fis 1 p和细胞周期之间存在一致的关系，因为fis 1 Delta细胞在细胞周期进程中表现出G（2）/M延迟。fis 1 Delta表型，包括细胞周期延迟，被GDAP 1完全拯救。相比之下，临床错义突变拯救了fis 1 Delta表型，除了细胞周期延迟。此外，Fis 1 p和人GDAP 1分别与β-微管蛋白Tub 2 p和TUBB相互作用。fis 1基因的缺陷可能导致线粒体在有丝分裂过程中的异常定位，由于其与来自有丝分裂纺锤体的微管的异常相互作用，导致细胞周期延迟在G（2）/M。在GDAP 1缺陷的神经元的情况下，线粒体和微管细胞骨架之间的相互作用将被改变，这可能会影响线粒体轴突运输和细胞内的运动，并可能解释GDAP 1相关的腓骨肌萎缩症的病理生理学。
Mutations in the GDAP1 gene are responsible of the Charcot-Marie-Tooth CMT4A, ARCMT2K, and CMT2K variants. GDAP1 is a mitochondrial outer membrane protein that has been related to the fission pathway of the mitochondrial network dynamics. As mitochondrial dynamics is a conserved process, we reasoned that expressing GDAP1 in Saccharomyces cerevisiae strains defective for genes involved in mitochondrial fission or fusion could increase our knowledge of GDAP1 function. We discovered a consistent relation between Fis1p and the cell cycle because fis1 Delta cells showed G(2)/M delay during cell cycle progression. The fis1 Delta phenotype, which includes cell cycle delay, was fully rescued by GDAP1. By contrast, clinical missense mutations rescued the fis1 Delta phenotype except for the cell cycle delay. In addition, both Fis1p and human GDAP1 interacted with beta-tubulins Tub2p and TUBB, respectively. A defect in the fis1 gene may induce abnormal location of mitochondria during budding mitosis, causing the cell cycle delay at G(2)/M due to its anomalous interaction with microtubules from the mitotic spindle. In the case of neurons harboring defects in GDAP1, the interaction between mitochondria and the microtubule cytoskeleton would be altered, which might affect mitochondrial axonal transport and movement within the cell and may explain the pathophysiology of the GDAP1-related Charcot-Marie-Tooth disease.