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作者：刘洁华中科技大学

学位级别：硕士

目的:肝星状细胞活化是肝纤维化发生发展的关键机制,其活化过程中发生的表型改变已获得认识,但是导致这一系列表型改变的精细机制仍知之甚少。本课题组前期已证实缺氧诱导因子-1(Hif-1)通过调节自噬影响肝星状细胞的活化,通过全基因组... 详细信息

目的:肝星状细胞活化是肝纤维化发生发展的关键机制,其活化过程中发生的表型改变已获得认识,但是导致这一系列表型改变的精细机制仍知之甚少。本课题组前期已证实缺氧诱导因子-1(Hif-1)通过调节自噬影响肝星状细胞的活化,通过全基因组表达芯片分析缺氧诱导的肝星状细胞内自噬相关基因的表达,筛选到与自噬相关的bnip3(Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3)蛋白。在此基础上开展本课题,旨在探讨核转录因子Hif-1靶基因bnip3调控肝星状细胞活化和自噬的可能机制,以进一步揭示肝纤维化发生发展的相关机制,寻找逆转肝纤维化的靶点。方法:采用氯化钴(CoCl)化学诱导缺氧法刺激人肝星状细胞系LX-2细胞,qPCR和Western blot检测LX-2细胞中bnip3的表达;以日本血吸虫感染小鼠为肝纤维化动物模型,用免疫组织化学染色法检测小鼠肝脏组织中bnip3的表达;对LX-2进行缺氧处理,Western blot检测P62、α-SMA以及LC3B表达,免疫荧光染色技术检测P62,观察LX-2细胞自噬;用Hif-1抑制剂YC-1抑制Hif-1的表达,缺氧或LPS刺激LX-2细胞,用Western blot和免疫荧光染色激光共聚焦显微镜检测bnip3表达;用特异性siRNA干扰bnip3表达,用Western blot检测LX2在缺氧或LPS刺激下α-SMA、LC3B表达;胶原酶消化-Percoll分离法分离BALB/c小鼠的原代肝星状细胞,用Western blot检测原代肝星状细胞自然活化过程中Hif-1、bnip3和自噬相关分子LC3B和P62以及活化相关分子α-SMA的表达,用免疫荧光染色激光共聚焦显微镜检测GFAP、bnip3及P62的表达;在原代肝星状细胞体外自然活化过程中加入Hif-1抑制剂YC-1,Western blot和免疫荧光染色激光共聚焦显微镜检测bnip3的表达,用特异性siRNA干扰bnip3表达,Western blot检测原代肝星状细胞自然活化过程中α-SMA和LC3B表达。结果:缺氧处理的人肝星状细胞LX-2和血吸虫肝纤维化小鼠肝脏组织中bnip3分子表达升高;LX-2缺氧处理后发生自噬;抑制LX-2细胞中Hif-1α表达可减少bnip3的表达;干扰LX-2细胞中bnip3表达可阻抑LX-2细胞自噬发生并抑制细胞活化;小鼠原代肝星状细胞在体外自然活化过程中bnip3表达升高;原代肝星状细胞自然活化过程中发生自噬且Hif-1α表达升高;抑制原代肝星状细胞中Hif-1α表达,bnip3表达不再升高;干扰原代肝星状细胞中bnip3表达,影响肝星状细胞活化和自噬发生。结论:Hif-1通过靶分子bnip3调控的肝星状细胞活化和自噬。

关键词：肝纤维化肝星状细胞自噬 Hif-1 bnip3

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SUMO1修饰Drp1促bnip3依赖性线粒体铁源性ROS介导Apelin-13诱导心肌细胞肥大

SUMO1修饰Drp1促BNIP3依赖性线粒体铁源性ROS介导Apelin-13诱导心...

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作者：唐名珠南华大学

学位级别：硕士

目的:APJ是与血管紧张素受体有同源性的G蛋白偶联受体,Apelin是其内源性配体。研究发现Apelin/APJ系统参与心力衰竭、高血压等心血管疾病。本实验室前期研究发现Apelin-13通过铁自噬-SFXN1依赖性线粒体铁超载途径促心肌细胞肥大。线粒... 详细信息

目的:APJ是与血管紧张素受体有同源性的G蛋白偶联受体,Apelin是其内源性配体。研究发现Apelin/APJ系统参与心力衰竭、高血压等心血管疾病。本实验室前期研究发现Apelin-13通过铁自噬-SFXN1依赖性线粒体铁超载途径促心肌细胞肥大。线粒体自噬（Mitophagy）作为特异性清除损伤线粒体的选择性自噬过程,同时参与诱导线粒体铁代谢紊乱和ROS的产生。本课题拟研究Apelin-13对线粒体自噬以及的bnip3依赖性线粒体自噬途径对Apelin-13诱导的铁源性ROS影响,并在前期研究基础上探讨SUMO1修饰Drp1促bnip3依赖性线粒体铁源性ROS途径是否参与Apelin-13诱导心肌细胞肥大,揭示Apelin-13/APJ系统诱导心肌肥厚的新分子机理,为进一步阐明APJ受体能否成为抗心肌肥厚疾病的新靶标提供理论依据。方法:1、Western Blot:检测大鼠H9c2心肌细胞Beclin 1,LC3II/I,bnip3,Drp1,SUMO1,BNP的表达;2、RNA干扰:设计RNA干扰链分别干扰H9c2心肌细胞中SUMO1,Drp1,bnip3的表达;3、Mito-SOX荧光探针检测H9c2大鼠心肌细胞中线粒体ROS的含量变化;4、RPA线粒体铁荧光探针观察H9c2心肌细胞中线粒体螯合铁的含量;5、免疫荧光观察SUMO1和Drp1共定位;bnip3和LC3B共定位;bnip3和线粒体共定位;6、透射电镜观察线粒体自噬的发生;7、ScepterTM细胞计数仪测量H9c2大鼠心肌细胞的直径和体积;8、BCA细胞定量试剂盒测定H9c2大鼠心肌细胞中的蛋白含量;9、免疫组化观察人尸检心肌肥厚心脏组织、双肾双夹大鼠肾血管性高血压模型大鼠心脏组织以及外源性注射Apelin-13的C57BL/6J小鼠心脏组织中BNP,SUMO1,Drp1,bnip3蛋白的表达;结果:1、Apelin-13以剂量和时间依赖性促进H9c2大鼠心肌细胞中线粒体自噬标志蛋白bnip3的表达;APJ拮抗剂F13A拮抗Apelin-13对bnip3的作用;2、透射电子显微镜下发现Apelin-13诱导H9c2大鼠心肌细胞中线粒体自噬的发生;3、Apelin-13以剂量及时间依赖性促进H9c2大鼠细胞中线粒体分裂蛋白Drp1的表达;APJ拮抗剂F13A逆转Apelin-13对Drp1的作用;4、Drp1特异性抑制剂Mdivi-1显著降低Apelin-13诱导的线粒体分裂蛋白Drp1、线粒体自噬标志蛋白bnip3和自噬标志蛋白Beclin 1、LC3II/I的表达;5、Drp1特异性抑制剂Mdivi-1显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和自噬标志蛋白LC3II的共定位;Drp1特异性抑制剂Mdivi-1显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和线粒体的共定位;6、Drp1-siRNA显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和自噬标志蛋白Beclin 1、LC3II/I的表达;7、Drp1-siRNA显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和自噬标志蛋白LC3II/I的共定位;Drp1-siRNA显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和线粒体的共定位;Drp1-siRNA显著抑制Apelin-13促进的线粒体铁及线粒体ROS的生成增加;8、Apelin-13以剂量与时间依赖性促进H9c2大鼠细胞中类泛素化蛋白SUMO1的表达;APJ拮抗剂F13A逆转Apelin-13对SUMO1的促进作用;9、Apelin-13促进SUMO1与Drp1的共定位;10、SUMO1-siRNA显著抑制Apelin-13诱导的线粒体分裂蛋白Drp1、线粒体自噬标志蛋白bnip3和自噬标志蛋白Beclin 1、LC3II/I的表达;11、SUMO1-siRNA显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和自噬标志蛋白LC3II的共定位;SUMO1-siRNA显著抑制Apelin-13诱导的线粒体自噬标志蛋白bnip3和线粒体的共定位;SUMO1-siRNA显著抑制Apelin-13促进的线粒体铁及线粒体ROS的生成增加;12、bnip3-siRNA抑制Apelin-13诱导的线粒体铁及线粒体ROS的生成增加;13、线粒体靶向抗氧化剂Mito-TEMPO显著抑制Apelin-13诱导的类泛素化蛋白SUMO1、线粒体分裂蛋白Drp1、线粒体自噬标志蛋白bnip3和自噬标志蛋白Beclin 1、LC3II/I的表达;14、线粒体靶向抗氧化剂Mito-TEMPO显著抑制Apelin-13诱导的SUMO1与Drp1,线粒体自噬标志蛋白bnip3和自噬标志蛋白LC3II的

关键词： Apelin-13 SUMO化修饰 Drp1 bnip3 线粒体自噬线粒体铁源性ROS 心肌细胞肥大

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HIF-1α/bnip3通路对类中性粒细胞自噬、凋亡的影响

HIF-1α/BNIP3通路对类中性粒细胞自噬、凋亡的影响

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作者：梁丽霞南华大学

学位级别：硕士

目的:在细胞水平上探索HIF-1α/bnip3通路对类中性粒细胞自噬、凋亡的影响,为中性粒细胞性哮喘发病机制的研究提供理论依据。方法:1.类中性粒细胞诱导分化:培养人急性早幼粒白血病细胞(HL-60),取对数生长期的HL-60细胞加入1.3%DMSO培养... 详细信息

目的:在细胞水平上探索HIF-1α/bnip3通路对类中性粒细胞自噬、凋亡的影响,为中性粒细胞性哮喘发病机制的研究提供理论依据。方法:1.类中性粒细胞诱导分化:培养人急性早幼粒白血病细胞(HL-60),取对数生长期的HL-60细胞加入1.3%DMSO培养4天后,Diff染色检测细胞形态,流式细胞术检测CD11b表达水平,确定类中性粒细胞是否诱导成功;2.构建IL-8培养下的类中性粒细胞模型:HL-60细胞诱导分化为类中性粒细胞后加入0ng/ml、100ng/ml、200ng/ml、400ng/m L、800ng/ml浓度的IL-8培养24h,流式细胞术检测类中性粒细胞的凋亡率,选择凋亡率最低组的IL-8浓度与类中性粒细胞培养0h、6h、12h、24h、48h,检测各组类中性粒细胞的凋亡率,选择凋亡率最低的组进行下一步实验;3.验证HIF-1α调控bnip3对类中性粒细胞自噬、凋亡的影响:分为6个组:1.空白组***-8组***-8+HIF-1α组***-8+HIF-1α-vector组***-8+HIF-1αsi RNA组***-8+HIF-1αsi RNA-vector组,分别用Western-blot、RT-q PCR方法检测每组HIF-1α、bnip3、LC3Ⅱ的表达水平,用流式细胞术检测类中性粒细胞凋亡率,用免疫荧光检测细胞内LC3Ⅱ的表达情况。结果:1.1.3%二甲基亚砜(DMSO)诱导HL-60细胞4天后,迪夫染色鉴定细胞核呈肾形、分叶核改变;流式细胞术检测发现诱导组CD11b蛋白的表达较空白组明显增加(p<0.01),说明类中性粒细胞诱导成功。2.流式细胞术检测不同IL-8浓度和培养时间组的类中性粒细胞凋亡率,发现400ng/ml、24h组类中性粒细胞凋亡率较低(p<0.05)。3.通过Western-blot、RT-q PCR、流式细胞术、免疫荧光检测发现:(1)IL-8组与空白组相比较:Western-blot、RT-q PCR结果显示HIF-1α、bnip3和LC3Ⅱ表达增加(P<0.05),流式细胞术结果显示类中性粒细胞凋亡率下降(P<0.05),免疫荧光提示LC3Ⅱ表达增多;(2)IL-8+HIF-1α组与IL-8组、IL-8+HIF-1α-vector组相比较:Western-blot、RT-q PCR结果显示HIF-1α、bnip3和LC3Ⅱ表达明显增加(P<0.05),流式细胞术结果显示凋亡率明显下降(P<0.05),免疫荧光提示LC3Ⅱ表达增多;(3)IL-8+HIF-1αsi RNA组与IL-8组、IL-8+HIF-1αsi RNA-vector组相比较:Western-blot、RT-q PCR结果显示HIF-1α、bnip3和LC3Ⅱ表达明显减少(P<0.05),流式细胞术结果显示类中性粒细胞凋亡率增加(P<0.05),免疫荧光提示LC3Ⅱ表达减少。结论:***-8可诱导类中性粒细胞自噬增加、凋亡抑制;***-1α/bnip3通路可诱导类中性粒细胞自噬增加、凋亡抑制;***-8可能通过HIF-1α/bnip3通路诱导类中性粒细胞自噬增加、凋亡抑制。

关键词：类中性粒细胞 HIF-1α bnip3 自噬凋亡

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bnip3 promotes the motility and migration of keratinocyte under hypoxia

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EXPERIMENTAL DERMATOLOGY 2017年第5期26卷 416-422页

作者： Zhang, Junhui Zhang, Dongxia Yan, Tiantian Jiang, Xupin Zhang, Can Zhao, Liping Li, Lingfei Tang, Di Zhang, Qiong Jia, Jiezhi Zhang, Jiaping Huang, Yuesheng Third Mil Med Univ Inst Burn Res Southwest Hosp State Key Lab Trauma Burns & Combined Injury Chongqing Peoples R China

The migration of keratinocytes from wound margins plays a critical role in the re-epithelialization of skin wounds. Hypoxia occurs immediately after injury and acts as an early stimulus to initiate the healing processes. Although our previous studies have revealed that hypoxia promotes keratinocyte migration, the precise mechanisms involved remain unclear. Here, we found that bnip3 expression was upregulated in hypoxic keratinocytes, and bnip3 silencing suppressed hypoxia-induced cell migration. Additionally, hypoxia activated the focal adhesion kinase (FAK) pathway through upregulation of bnip3, while FAK inhibition attenuated hypoxic keratinocyte migration. Here, we conclusively demonstrate a novel role for bnip3 in hypoxia-induced keratinocyte migration. Furthermore, we provide a new perspective on the molecular mechanisms of wound healing and identify bnip3 as a potential new molecular target for clinical treatments to enhance wound healing.

关键词： bnip3 cell migration cell motility focal adhesion kinase hypoxia

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bnip3, a cell pro-apoptotic protein, involved in response to viral infection in orange spotted grouper, Epinephelus coioides

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FISH & SHELLFISH IMMUNOLOGY 2017年 64卷 407-413页

作者： Cai, Jia Wei, Shina Yu, Dapeng Song, Rui Lu, Yishan Wu, Zaohe Qin, Qiwei Jian, Jichang Guangdong Ocean Univ Coll Fishery 1 Haida Rd Zhanjiang 524088 Guangdong Peoples R China Guangdong Prov Key Lab Pathogen Biol & Epidemiol Zhanjiang 524088 Peoples R China Guangdong Key Lab Control Dis Aquat Econ Anim Zhanjiang 524088 Peoples R China Chinese Acad Sci Key Lab Trop Marine Bioresources & Ecol South China Sea Inst Oceanol 164 West Xingang Rd Guangzhou 510301 Guangdong Peoples R China South China Agr Univ Coll Marine Sci Guangzhou 510642 Guangdong Peoples R China Hunan Fisheries Sci Inst Changsha 410153 Hunan Peoples R China

bnip3 is a kind of BH3-only protein that induces both cell death and autophagy. Here, a bnip3 gene (Ecbnip3) was identified from orange spotted grouper, Epinephelus coioides. Ecbnip3 possessed 236 amino acids residues, contained a conservative bnip3 domain and a transmembrane region. Besides, Ecbnip3 expressed at a relative high level in heart and spleen. Ecbnip3 transcript was up-regulated after SGIV infection in vitro. Subcellular localization analysis revealed that Ecbnip3 was predominantly localized in the cytoplasm and co-localized with mitochondria. In addition, overexpression Ecbnip3 accelerated SGIV infection induced cell death but inhibited viral genes transcription. Taken together, these results provided new evidence that fish bnip3 might involved in response to virus infection. (C) 2017 Published by Elsevier Ltd.

关键词： Epinephelus coioides bnip3 Singapore grouper iridovirus (SGIV) Viral infection

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bnip3 induces apoptosis and protective autophagy under hypoxia in esophageal squamous cell carcinoma cell lines: bnip3 regulates cell death

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DISEASES OF THE ESOPHAGUS 2017年第9期30卷 1-8页

作者： Ma, Z. Chen, C. Tang, P. Zhang, H. Yue, J. Yu, Z. Tianjin Med Univ Canc Inst & Hosp Natl Clin Res Ctr CancKey Lab Prevent & Therapy Tianjins Clin Res Ctr CancDept Esophageal Canc Tianjin Peoples R China

Bcl-2/adenovirus E1B 19-kDa interacting protein (bnip3), a pro-apoptosis protein regulated by the methylation status of its promoter, has been implicated in inducing autophagy. However, the roles of bnip3 and bnip3-induced autophagy under hypoxia remain uncertain in esophageal squamous cell carcinoma (ESCC). Two esophageal squamous cancer cell lines, CAES17 and KYSE140, were selected on the basis of the expression and methylation status of bnip3 to investigate the features of bnip3 under hypoxia. Hypoxia increased cell death and the expression of bnip3, whose promoter status was lower methylation, in a time-dependent manner. bnip3 knockdown by RNA interference downregulated cell death. These studies demonstrated that the exposure of ESCC cells to hypoxia increased the autophagic punctate distribution of MDC staining and GFP-LC3 and that autophagy rate could be inhibited by bnip3-siRNA. In addition, under hypoxia, cells transfected with bnip3-siRNA exhibited a lower apoptosis rate than the control, and the apoptosis induced by bnip3 exhibited a caspase-independent manner. Furthermore, the administration of the autophagic inhibitor 3-methyladenine (3-MA) could augment bnip3-induced cell apoptosis and death, suggesting that autophagy plays a protective role under hypoxia. Together, our studies indicated that bnip3 exerts prodeath effects through the induction of caspase-independent apoptosis under hypoxia in ESCC, though bnip3-induced autophagy acting as a survival mechanism.

关键词： apoptosis autophagy bnip3 esophageal cancer hypoxia

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Hyperoside protects against hypoxia/reoxygenation induced injury in cardiomyocytes by suppressing the bnip3 expression

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GENE 2017年 629卷 86-91页

作者： Xiao, Rui Xiang, An-Li Pang, Hong-Bo Liu, Ke-Qiang Hubei Prov Hosp Integrated Chinese & Western Med Wuhan 430015 Hubei Peoples R China Tianjin Univ Tradit Chinese Med Tianjin 300193 Peoples R China Wuhan Univ Sci & Technol City Coll Wuhan 430083 Hubei Peoples R China Tianjin Union Med Ctr Tianjin 300191 Peoples R China

Aims: Role of hyperoside in protecting cardiomyocytes from ischemia/reperfusion induced injury has been proved. However, possible protecting mechanisms remain unclear. To fix the problem, an essential pro-apoptotic protein bnip3 was studied in our experiments. Methods and results: Neonatal rat cardiomyocytes were used and submitted to hypoxia for 8 h followed by re oxygenation for 2 h to simulate the ischemia/reperfusion injury. Hypoxia/reoxygenation(H/R) induced damage to cardiomyocytes and the protective effect of hyperoside were examined by means of MTT assay. H/R-induced apoptosis was assessed by Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling(TUNEL) and DNA Ladder assay. mRNA expression of bnip3 was determined by use of quantitative real-time reverse transcription polymerase chain reaction assay. Protein levels of bnip3, Bax, Bcl-2 and cleaved caspase-3 *** using western-blot assay. Our results showed that H/R caused great damage to cardiomyocytes, upregulated the protein expressions of bnip3, Bax, cleaved caspase3, and decreased the expression of the antiapoptotic protein of Bcl-2. Whereas, compared with the H/R group, a decrease in activities of bnip3, Bax, cleaved caspase3, and a promoting expression of Bcl-2 were detected in the H/R goup pretreated with hyperoside. Conclusion: It was concluded in our study that H/R-induced apoptotic effect in cardiomyocytes could be attenuated by hyperoside, and the protective role of hyperoside, if not completely, could be partly through the suppression of the pro-apoptotic gene bnip3.

关键词： Hyperoside Hypoxia/reoxygenation Apoptosis bnip3

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Ellagic acid antagonizes bnip3-mediated mitochondrial injury and necrotic cell death of cardiac myocytes

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FREE RADICAL BIOLOGY AND MEDICINE 2017年 112卷 411-422页

作者： Dhingra, Abhinav Jayas, Rahul Afshar, Pegah Guberman, Matthew Maddaford, Graham Gerstein, Johnathan Lieberman, Brooke Nepon, Hilary Margulets, Victoria Dhingra, Rimpy Kirshenbaum, Lorrie A. St Boniface Gen Hosp Albrechtsen Res Ctr Dept Physiol & Pathophysiol Inst Cardiovasc Sci Winnipeg MB Canada Univ Manitoba Coll Med Fac Hlth Sci Winnipeg MB R2H 2H6 Canada

The Bcl-2 protein bnip3 is crucial for provoking oxidative injury to mitochondria following anthracycline treatment or ischemia-reperfusion injury. Herein, we investigate the effects of the polyphenolic compound ellagic acid (EA) on bnip3 mediated mitochondrial injury and necrotic cell death in cardiac myocytes. In contrast to vehicle treated cardiomyocytes, bnip3 was highly enriched in mitochondrial fractions of cardiac myocytes treated with the anthracycline doxorubicin or in cells subjected to hypoxia (HPX). Mitochondrial associated bnip3 was accompanied by mPTP opening and loss of Delta psi m. The dynamin related fission protein Drp-1 was phosphorylated (Drp1(616)) and coincided with excessive mitochondrial fragmentation, mitophagy and necrosis in cardiac myocytes treated with doxorubicin or subjected to hypoxia. Moreover, knock-down of bnip3 was sufficient to prevent mitochondrial fission and doxorubicin-induced cell death supporting the involvement of bnip3 in doxorubicin cardiotoxity. Interestingly, mitochondrial associated bnip3 in cells treated with doxorubicin was markedly reduced by EA. This resulted in significantly less mitochondrial fission and cell death. Notably, EA similarly suppressed mitochondrial injury and cell death induced by hypoxia or bnip3 over-expression. Herein, we identify a novel signaling axis that operationally links EA and bnip3 for suppression of cardiac cell death. We provide compelling new evidence that EA suppresses mitochondrial injury and necrotic cell death of cardiac myocytes by functionally abrogating bnip3 activity. Hence, by suppressing mitochondrial injury induced by bnip3, EA may provide a therapeutic advantage in reducing oxidative injury and cardiac dysfunction in cancer patients undergoing anthracycline treatment or individuals with ischemic cardiac stress.

关键词： Ventricular myocytes Oxidative stress Mitochondria Mitophagy Cell death bnip3

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OPA1 haploinsufficiency induces a bnip3-dependent decrease in mitophagy in neurons: relevance to Dominant Optic Atrophy

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JOURNAL OF NEUROCHEMISTRY 2017年第3期140卷 485-494页

作者： Moulis, Manon F. Millet, Aurelie M. Daloyau, Marlene Miquel, Marie-Christine Ronsin, Brice Wissinger, Bernd Arnaune-Pelloqin, Laetitia Belenguer, Pascale Toulouse Univ Ctr Integrat Biol CBI Res Ctr Anim Cognit CRCA CNRSUPS Toulouse France Toulouse Univ Ctr Integrat Biol CBI Ctr Dev Biol CBD CNRSUPS Toulouse France Univ Tubingen Ctr Ophthalmol Tubingen Germany

Dominant optic atrophy (DOA) is because of mutations in the mitochondrial protein OPA1. The disease principally affects retinal ganglion cells, whose axons degenerate leading to vision impairments, and sometimes other neuronal phenotypes. The exact mechanisms underlying DOA pathogenesis are not known. We previously demonstrated that the main role of OPA1, as a mitochondrial fusogenic and anti-apoptotic protein, are inhibited by interaction with the stress inducible pro-apoptotic bnip3 protein. Because bnip3 was recently reported to participate in autophagy and mitophagy, we tested the involvement of these processes in DOA pathogenesis. Using an invitro neuronal model of DOA, we identified a bnip3 down-regulation that reduced autophagy and mitophagy. Restoring bnip3 had a biphasic effect, first rescuing autophagy and mitophagy levels but later leading to cell death. Similarly, in an invivo mouse model of DOA, we showed that bnip3 levels are decreased in young adult mice and increase to normal levels upon aging, paralleling disease progression. Altogether, our results indicate that the relationship between OPA1 and bnip3 may have important bearings on DOA pathogenesis.

关键词： bnip3 dominant optic atrophy mitochondria mitochondrial dynamics mitophagy neurodegenerative diseases OPA1

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Popdc1/Bves Functions in the Preservation of Cardiomyocyte Viability While Affecting Rac1 Activity and bnip3 Expression

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JOURNAL OF CELLULAR BIOCHEMISTRY 2017年第6期118卷 1505-1517页

作者： Kliminski, Vitaly Uziel, Orit Kessler-Icekson, Gania Tel Aviv Univ Sackler Fac Med Felsenstein Med Res Ctr Tel Aviv Israel Tel Aviv Univ Rabin Med Ctr Tel Aviv Israel

The Popeye domain containing1, also called Bves (Popdc1/Bves), is a transmembrane protein that functions in muscle regeneration, heart rate regulation, hypoxia tolerance, and ischemia preconditioning. The expression of Popdc1/Bves is elevated in cardiomyocytes maintained in serum free defined medium. We hypothesized that Popdc1/Bves is important for cardiomyocyte survival under the stress of serum deprivation and investigated the mechanisms involved. A deficit in Popdc1/Bves, achieved by siRNA-mediated gene silencing, results in cardiomyocyte injury and death, upregulation of the pro-apoptotic protein Bcl-2/adenovirus E1B 19-kDa interacting protein3 (bnip3), as well as reduction in Rac1-GTPase activity and in Akt phosphorylation. Combined Popdc1/Bves and bnip3 silencing attenuated cell injury and prevented bnip3 upregulation induced by the silencing of Popdc1/Bves alone. Chromatin immunoprecipitation indicated an increased binding of the transcription factor FoxO3 to the bnip3 promoter although augmentation of FoxO3 in the nuclei was not detected. By contrast, the transcription factor NFB was excluded from the nuclei of Popdc1/Bves deficient cardiomyocytes and exhibited decreased binding to the bnip3 promoter. The data indicates that Popdc1/Bves plays a role in the preservation of cardiomyocyte viability under serum deficiency through the alteration of Rac1 activity and the regulation of bnip3 expression by FoxO3 and NFB transcription factors pointing to Popdc1/Bves as a potential target to enhance heart protection. J. Cell. Biochem. 118: 1505-1517, 2017. (C) 2016 Wiley Periodicals, Inc.

关键词： CARDIOMYOCYTES Popdc1/Bves CELL VIABILITY bnip3 Rac1

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