SPG20 protein spartin associates with cardiolipin via its plant-related senescence domain and regulates mitochondrial Ca2+ homeostasis.
SPG20 protein spartin associates with cardiolipin via its plant-related senescence domain and regulates mitochondrial Ca2+ homeostasis.
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DOI：
10.1371/journal.pone.0019290
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Bakowska JC
中科院分区：
文献类型：
--
作者：
Joshi DC;Bakowska JC
遗传性痉挛性截瘫（HSPs）是一组神经系统疾病，临床表现为下肢痉挛，病理表现为皮质脊髓束变性。Troyer综合征是一种常染色体隐性热休克，由spartin （SPG20）基因的移码突变引起。先前，我们确定这种突变导致缺乏表达的截断突变的spartin蛋白。Spartin参与许多细胞过程，并与包括线粒体在内的几种细胞内细胞器相关。Spartin在其c端含有一个保守的与植物相关的衰老结构域。然而，这个结构域的功能和spartin在线粒体生理学中的作用目前都不清楚。在这项研究中，我们确定了spartin的植物相关衰老结构域与心磷脂相互作用，但不与其他两种主要的线粒体磷脂，磷脂酰胆碱和磷脂酰乙醇胺相互作用。我们还发现，在人神经母细胞瘤细胞系中，小干扰RNA敲低spartin可导致线粒体膜去极化。此外，spartin的消耗导致thapsigargin处理的细胞线粒体钙摄取和线粒体膜电位的显著降低。我们的研究结果表明，线粒体钙摄取的损害可能有助于长皮质脊髓轴突的神经退行性变和Troyer综合征的病理生理。
Hereditary spastic paraplegias (HSPs) are a group of neurological disorders characterized clinically by spasticity of lower limbs and pathologically by degeneration of the corticospinal tract. Troyer syndrome is an autosomal recessive HSP caused by a frameshift mutation in the spartin (SPG20) gene. Previously, we established that this mutation results in a lack of expression of the truncated mutant spartin protein. Spartin is involved in many cellular processes and associates with several intracellular organelles, including mitochondria. Spartin contains a conserved plant-related senescence domain at its C-terminus. However, neither the function of this domain nor the roles of spartin in mitochondrial physiology are currently known. In this study, we determined that the plant-related senescence domain of spartin interacts with cardiolipin but not with two other major mitochondrial phospholipids, phosphatidylcholine and phosphatidylethanolamine. We also found that knockdown of spartin by small interfering RNA in a human neuroblastoma cell line resulted in depolarization of the mitochondrial membrane. In addition, depletion of spartin resulted in a significant decrease in both mitochondrial calcium uptake and mitochondrial membrane potential in cells treated with thapsigargin. Our results suggest that impairment of mitochondrial calcium uptake might contribute to the neurodegeneration of long corticospinal axons and the pathophysiology of Troyer syndrome.
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