Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator
Sym1, the yeast ortholog of the MPV17 human disease protein, is a stress-induced bioenergetic and morphogenetic mitochondrial modulator
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DOI：
10.1093/hmg/ddp581
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发表时间：
2010-03-15
影响因子：
3.5
通讯作者：
Donnini, Claudia
中科院分区：
文献类型：
--
作者：
Dallabona, Cristina;Marsano, Rene Massimiliano;Donnini, Claudia
一种特殊形式的肝脑mtDNA耗竭综合征是由MPV 17基因突变引起的，该基因编码一种位于线粒体内膜的功能未知的小疏水蛋白。为了确定与人类疾病相关的MPV 17变体的分子基础，我们先前利用S.酿酒酵母作为模型系统，这要归功于MPV 17直系同源基因SYM 1的存在。我们在这里证明，SYM 1基因产物是必不可少的，以维持OXPHOS，糖原储存，线粒体形态和mtDNA的稳定性，在应力条件下，如高温和乙醇依赖性生长。为了深入了解Sym 1-less表型的分子基础，我们鉴定并表征了多拷贝抑制基因和代谢抑制化合物。我们的研究结果表明：（i）代谢障碍和线粒体DNA不稳定性的发生相互独立的SYM 1消融的结果;（ii）SYM 1消融导致糖原储存的消耗，可能是由于有缺陷的回补流的三羧酸（TCA）循环中间体的细胞质;（iii）Sym 1缺陷细胞器中线粒体嵴的扁平化表明Sym 1在线粒体内膜的结构保存中的作用，这反过来又可以控制mtDNA的维持和稳定性。
A peculiar form of hepatocerebral mtDNA depletion syndrome is caused by mutations in the MPV17 gene, which encodes a small hydrophobic protein of unknown function located in the mitochondrial inner membrane. In order to define the molecular basis of MPV17 variants associated with the human disorder, we have previously taken advantage of S. cerevisiae as a model system thanks to the presence of an MPV17 ortholog gene, SYM1. We demonstrate here that the SYM1 gene product is essential to maintain OXPHOS, glycogen storage, mitochondrial morphology and mtDNA stability in stressing conditions such as high temperature and ethanol-dependent growth. To gain insight into the molecular basis of the Sym1-less phenotype, we identified and characterized multicopy suppressor genes and metabolic suppressor compounds. Our results suggest that (i) metabolic impairment and mtDNA instability occur independently from each other as a consequence of SYM1 ablation; ( ii) ablation of Sym1 causes depletion of glycogen storage, possibly due to defective anaplerotic flux of tricarboxylic acid (TCA) cycle intermediates to the cytosol; (iii) flattening of mitochondrial cristae in Sym1-defective organelles suggests a role for Sym1 in the structural preservation of the inner mitochondrial membrane, which could in turn control mtDNA maintenance and stability.