Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
Faculty of Health Sciences, University of Macau, Taipa, China.
Autophagy. 2021 Oct;17(10):2783-2799. doi: 10.1080/15548627.2020.1841953. Epub 2020 Nov 9.
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. AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Baf: bafilomycin A; 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.
自噬（以下简称自噬）是细胞内大量降解无用物质的过程，在癌症、动脉粥样硬化和神经退行性疾病等许多疾病中常被失调。因此，自噬调节剂具有成为与自噬相关疾病的治疗剂的巨大潜力。在这里，我们报告抗抑郁药舍曲林（Sert）是一种自噬诱导剂。在机制上，Sert 可能与线粒体 VDAC1（电压依赖性阴离子通道 1）结合并拮抗，导致细胞内 ATP（三磷酸腺苷）水平降低，激活 AMP 激活的蛋白激酶（AMPK）并抑制其下游 MTOR（雷帕霉素靶蛋白激酶）-RPS6KB1（核糖体蛋白 S6 激酶 B1）信号通路。缺乏 VDAC1 表达的细胞完全消除 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 通过诱导自噬来促进 MAPT（微管相关蛋白 tau）蛋白的自噬降解来抑制 tau 病。我们的研究表明 Sert 作为一种新型小分子自噬诱导剂具有潜力，并通过靶向 VDAC1 为治疗自噬相关疾病提供了一种新的候选药物。AMP：单磷酸腺苷；AMPK：AMP 激活的蛋白激酶；ATP：三磷酸腺苷；Baf：巴佛洛霉素 A；BiFC：生物分子荧光互补；CAMKK2/CAMKKB：钙/钙调蛋白依赖性蛋白激酶激酶 2；CC：化合物 C；DARTS：药物亲和反应靶稳定性；HUVECs：人脐静脉内皮细胞；Inda：吲哚拉明；STK11/LKB1：丝氨酸/苏氨酸激酶 11；MAPT：微管相关蛋白 tau；MAP1LC3/LC3：微管相关蛋白 1 轻链 3；3-MA：3-甲基腺嘌呤；MEFs：小鼠胚胎成纤维细胞；MTOR：雷帕霉素靶蛋白激酶；PI3K：磷酸肌醇 3-激酶；Rapa：雷帕霉素；Sert：舍曲林；RPS6KB1：核糖体蛋白 S6 激酶 B1；SQSTM1/p62：自噬体 1；SLC6A4/SERT1：溶质载体家族 6 成员 4；TFEB：转录因子 EB；VDAC1：电压依赖性阴离子通道 1；WT：野生型；WM：渥曼青霉素。
