Oxidative stress-induced apoptosis in peripheral blood lymphocytes from patients with POLG-related disorders
Oxidative stress-induced apoptosis in peripheral blood lymphocytes from patients with POLG-related disorders
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DOI：
10.1016/j.jns.2016.07.047
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发表时间：
2016-09-15
影响因子：
4.4
通讯作者：
Federico, Antonio
中科院分区：
文献类型：
--
作者：
Formichi, Patrizia;Radi, Elena;Federico, Antonio
背景资料：POLG相关疾病是一组异质性疾病，其特征在于重叠的临床表现，并与POLG基因突变相关。POLG编码线粒体聚合酶γ（POLG）的催化亚基，对线粒体DNA（mtDNA）的复制和修复至关重要。对突变型POLG小鼠的研究表明，氧化应激和细胞凋亡增加。在这方面，我们分析了POLG突变在细胞凋亡调节中的参与，评估了POLG相关疾病患者外周血淋巴细胞（PBL）的细胞凋亡。方法：细胞在基础条件下培养，并与2-脱氧-D-核糖（dRib），一种还原糖，诱导细胞凋亡的氧化应激。流式细胞术检测细胞凋亡率。同时分析了磷脂酰丝氨酸易位、线粒体膜去极化和caspase 3激活。结果：我们的数据显示，POLG突变患者经dRib治疗后，细胞凋亡百分比高于对照组，而在基础培养条件下，两组细胞凋亡水平相似。POW突变的细胞比对照细胞对氧化应激诱导的凋亡更敏感，证实mtDNA突变可能在线粒体凋亡途径中起作用。我们还认为，氧化还原状态稳态可能在POLG相关疾病的表型表达中起着至关重要的作用。(C)2016由Elsevier B. V.出版
Background: POLG-related disorders are a group of heterogeneous diseases characterized by an overlapping clinical presentations and associated with mutations in the POLG gene. POLG codes for the catalytic subunit of mitochondrial polymerase gamma (POLG), essential for mitochondrial DNA (mtDNA) replication and repair.Studies on mutator POLG mice showed an increase in oxidative stress and apoptosis.In this regard we analysed the involvement of POLG mutations in the apoptotic regulation, evaluating apoptosis in peripheral blood lymphocytes (PBLs) from patients with POLG-related diseases.Methods: Cells were cultured under basal conditions and with 2-deoxy-D-ribose (dRib), a reducing sugar that induces apoptosis by oxidative stress. Apoptosis rate was assessed by flow cytometty. Phosphatidylserine translocation, mitochondrial membrane depolarization and caspase 3 activation were also analysed.Results: Our data showed higher percentages of apoptosis after dRib treatment in patients with POLG mutations than in controls, while under basal culture conditions, apoptosis levels were similar in the two groups.Conclusions: Cells with POW mutations are more sensitive than control cells to oxidative stress-induced apoptosis, confirming that mtDNA mutations may have a role in mitochondrial apoptosis pathway. We also suggest that redox state homeostasis may play a crucial role in phenotypic expression of POLG-related diseases. (C) 2016 Published by Elsevier B.V.