Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein.
Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein.
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DOI：
10.1080/15548627.2020.1841953
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发表时间：
2021-10
期刊：
影响因子：
13.3
通讯作者：
Kwon HJ
中科院分区：
文献类型：
--
作者：
Hwang HY;Shim JS;Kim D;Kwon HJ
自噬（Macroautophagy/autophagy，以下称为自噬）是细胞内不必要的元素大量降解的过程，在许多疾病如癌症、动脉粥样硬化和神经退行性疾病中经常失调。因此，自噬调节剂具有很大的潜力，成为治疗自噬相关疾病的药物。在这里，我们报告说，抗肿瘤药物舍曲林（Sert）是一种自噬诱导剂。从机制上讲，Sert可能与线粒体VDAC 1（电压依赖性阴离子通道1）结合并拮抗，导致细胞ATP（三磷酸腺苷）水平降低，AMP活化蛋白激酶（AMPK）活化并抑制其下游MTOR（雷帕霉素激酶的机制靶点）-RPS 6 KB 1（核糖体蛋白S6激酶B1）信号通路。缺乏VDAC 1表达的细胞完全消除了Sert对AMPK-MTOR通路和自噬诱导活性的调节作用。我们进一步表明，Sert通过诱导自噬促进MAPT（微管相关蛋白tau）蛋白的自噬降解来抑制tau蛋白病。我们的研究证明了Sert作为一种新型小分子自噬诱导剂的潜力，并为通过靶向VDAC 1治疗自噬相关疾病提供了一种新的候选药物。缩略语：放大器：一磷酸腺苷; AMPK：AMP活化蛋白激酶;可承诺量：三磷酸腺苷; Baf：巴弗洛霉素A1; BiFC：生物分子荧光互补; CAMKK 2/CAMKKB：钙/钙调蛋白依赖性蛋白激酶激酶2; CC：化合物C; DARTS：药物亲和力响应性靶稳定性; HUVEC：人脐静脉内皮细胞; Inda：茚达曲林; STK 11/LKB 1：丝氨酸/苏氨酸激酶11; MAPT：微管相关蛋白tau; MAP 1 LC 3/LC 3：微管相关蛋白1轻链3; 3-MA：3-甲基腺嘌呤; MEF：小鼠胚胎成纤维细胞; MTOR：雷帕霉素激酶的机制靶标; PI 3 K：磷酸肌醇3-激酶; Rapa：雷帕霉素; Sert：舍曲林; RPS 6 KB 1：核糖体蛋白S6激酶B1; SQSTM 1/p62：多价螯合体1; SLC 6A 4/SERT 1：溶质载体家族6成员4; TFEB：转录因子EB; VDAC 1：电压依赖性阴离子通道1; WT：野生型; WM：渥曼青霉素。
Macroautophagy/autophagy (hereafter autophagy), the process of mass degradation of unnecessary elements within the cell, is often dysregulated in many diseases such as cancer, atherosclerosis, and neurodegenerative diseases. Hence, autophagy modulating agents have a great potential to be therapeutic agents for the autophagy-related diseases. Here we report that an anti-depressant drug sertraline (Sert) is an autophagy-inducing agent. Mechanistically, Sert potentially binds to and antagonizes the mitochondrial VDAC1 (voltage dependent anion channel 1), resulting in reduced cellular ATP (adenosine triphosphate) level, activation of AMP-activated protein kinase (AMPK) and inhibition of its downstream, MTOR (mechanistic target of rapamycin kinase)-RPS6KB1 (ribosomal protein S6 kinase B1) signaling pathway. Cells lacking VDAC1 expression completely abrogate the modulatory effect of Sert on AMPK-MTOR pathway and autophagy-inducing activity. We further show that Sert suppresses tauopathy by promoting the autophagic degradation of MAPT (microtubule associated protein tau) protein via inducing autophagy. Our study demonstrates the potential of Sert as a novel small molecule autophagy-inducing agent and provides a new drug candidate to treat autophagy related diseases by targeting VDAC1. Abbreviations: AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Baf: bafilomycin A1; BiFC: biomolecular fluorescence complementation; CAMKK2/CAMKKB: calcium/calmodulin dependent protein kinase kinase 2; CC: compound C; DARTS: drug affinity responsive target stability; HUVECs: human umbilical vein endothelial cells; Inda: indatraline; STK11/LKB1: serine/threonine kinase 11; MAPT: microtubule associated protein tau; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; 3-MA: 3-methyladenine; MEFs: mouse embryonic fibroblasts; MTOR: mechanistic target of rapamycin kinase; PI3K: phosphoinositide 3-kinase; Rapa: rapamycin; Sert: sertraline; RPS6KB1: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; SLC6A4/SERT1: solute carrier family 6 member 4; TFEB: transcription factor EB; VDAC1: voltage dependent anion channel 1; WT: wild-type; WM: wortmannin.
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7.8
作者：
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DOI：
10.1073/pnas.1512867112
发表时间：
2015-12-29
影响因子：
11.1
作者：
Head, Sarah A.;Shi, Wei;Liu, Jun O.
通讯作者：
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影响因子：
14.9
作者：
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