Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells
Differential effects of TSPO ligands on mitochondrial function in mouse microglia cells
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DOI：
10.1016/j.psyneuen.2019.03.029
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发表时间：
2019-08-01
影响因子：
3.7
通讯作者：
Wetzel, Christian H.
中科院分区：
文献类型：
--
作者：
Bader, Stefanie;Wolf, Luisa;Wetzel, Christian H.
转运蛋白18kda （TSPO）最初被描述为外周苯二氮卓受体，是一种保守的线粒体外膜蛋白，参与胆固醇转运，从而影响类固醇激素的生物合成，以及与生物能量学、氧化应激和Ca2+稳态相关的线粒体功能。TSPO在类固醇组织如肾上腺中高表达，但在中枢神经系统中低表达。在炎症、神经退行性变或癌症等各种疾病状态下，受影响组织中线粒体TSPO的表达上调。TSPO的表达可以通过高亲和力的放射性配体来追踪诊断目的。此外，TSPO的功能可由具有激动或拮抗性质的合成配体和内源性配体调节。因此，TSPO配体既是重要的生物标志物，也是公认的治疗剂。在本研究中，我们旨在表征TSPO配体对小鼠BV-2小胶质细胞（TSPO表达水平显著）的影响，并分析XBD173、PK11195和Ro5-4864以及炎症剂脂多糖（LPS）对神经类固醇合成和线粒体基本功能（如氧化磷酸化、线粒体膜电位和Ca2+稳态）的影响。通过比较慢病毒TSPO敲低与shRNA混乱对照和野生型BV-2细胞，将特异性TSPO依赖效应与脱靶效应分离开来。我们的数据证明了配体对不同细胞功能的特异性作用，以tspo依赖或独立的方式，为tspo介导的特异性和脱靶效应提供了证据。
The translocator protein 18 kDa (TSPO), initially characterized as peripheral benzodiazepine receptor, is a conserved outer mitochondrial membrane protein, implicated in cholesterol transport thereby affecting steroid hormone biosynthesis, as well as in general mitochondrial function related to bioenergetics, oxidative stress, and Ca2+ homeostasis. TSPO is highly expressed in steroidogenic tissues such as adrenal glands, but shows low expression in the central nervous system. During various disease states such as inflammation, neurodegeneration or cancer, the expression of mitochondrial TSPO in affected tissues is upregulated. The expression of TSPO can be traced for diagnostic purpose by high affinity radio-ligands. Moreover, the function of TSPO is modulated by synthetic as well as endogenous ligands with agonistic or antagonistic properties. Thus, TSPO ligands serve functions as both important biomarkers and putative therapeutic agents.In the present study, we aimed to characterize the effects of TSPO ligands on mouse BV-2 microglia cells, which express significant levels of TSPO, and analyzed the effect of XBD173, PK11195, and Ro5-4864, as well as the inflammatory reagent Lipopolysaccharides (LPS) on neurosteroid synthesis and on basic mitochondrial functions such as oxidative phosphorylation, mitochondrial membrane potential and Ca2+ homeostasis. Specific TSPO-dependent effects were separated from off-target effects by comparing lentiviral TSPO knockdown with shRNA scramble-controls and wild-type BV-2 cells. Our data demonstrate ligand-specific effects on different cellular functions in a TSPO-dependent or independent manner, providing evidence for both specific TSPO-mediated, as well as off-target effects.