Deletion of Mitochondrial Porin Alleviates Stress Sensitivity in the Yeast Model of Shwachman-Diamond Syndrome

作     者：Waruenada Kanprasoet Laran T.Jensen Suwimon Sriprach Kanate Thitiananpakorn Khanti Rattanapornsompong Amornrat Naranuntarat Jensen 

作者机构：Department of Pathobiology Faculty of Science Mahidol University Department of Biochemistry Faculty of Science Mahidol University Toxicology Graduate Program Faculty of Science Mahidol University 

出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)

年 卷 期：2015年第42卷第12期

页      面：671-684页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the Faculty of Science Mahidol University(ANJ) 

主　　题：Shwachman-Diamond syndrome Oxidative stress Yeast Porin Mitochondria 

摘      要：Shwachman-Diamond syndrome （SDS） is a multi-system disorder characterized by bone marrow failure, pancreatic insufficiency, skeletal abnormalities, and increased risk of leukemic transformation. Most patients with SDS contain mutations in the Shwachman- Bodian-Diamond syndrome gene （SBDS）, encoding a highly conserved protein that has been implicated in ribosome biogenesis. Emerging evidence also suggests a distinct role of SBDS beyond protein translation. Using the yeast model of SDS, we examined the underlying mechanisms that cause cells lacking Sdolp, the yeast SBDS ortholog, to exhibit reduced tolerance to various stress conditions. Our analysis indicates that the environmental stress response （ESR）, heat shock response （HSR）, and endoplasmic reticulum unfolded protein response （UPR） of sdolA cells are functional and that defects in these pathways do not produce the phenotypes observed in sdolh yeast. Depletion of mitochondlial DNA （mtDNA） was observed in sdolh cells, and this is a probable cause of the mitochondrial insufficiency in SDS. Prior disruption of POR1, encoding the mitochondrial voltage dependent anion channel （VDAC）, abrogated the effects of SD01 deletion and substantially restored resistance to environmental stressors and protected against damage to mtDNA. Conversely, wild-type cells over-expressing POR1 exhibited growth impairment and increased stress sensitivity similar to that seen in sdolA cells. Overall, our results suggest that specific VDAC inhibitors may have therapeutic benefits for SDS patients.