Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein

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.

巨自噬（macroautophagy，以下简称自噬）是细胞内冗余物质大规模降解的过程，在癌症、动脉粥样硬化、神经退行性疾病等多种疾病中常出现失调。因此，自噬调控剂具备成为自噬相关疾病治疗药物的巨大潜力。本研究发现抗抑郁药物舍曲林（sertraline，简称Sert）是一种自噬诱导剂。从机制上来说，舍曲林可结合并拮抗线粒体电压依赖性阴离子通道1（voltage dependent anion channel 1，VDAC1），进而导致细胞内三磷酸腺苷（adenosine triphosphate，ATP）水平降低，激活腺苷酸活化蛋白激酶（AMP-activated protein kinase，AMPK）并抑制其下游的雷帕霉素靶蛋白激酶（mechanistic target of rapamycin kinase，MTOR）-核糖体蛋白S6激酶B1（ribosomal protein S6 kinase B1，RPS6KB1）信号通路。缺失VDAC1表达的细胞可完全抵消舍曲林对AMPK-MTOR通路的调控作用及自噬诱导活性。本研究进一步证实，舍曲林可通过诱导自噬促进微管相关蛋白tau（microtubule associated protein tau，MAPT）的自噬性降解，从而抑制tau蛋白病。本研究证明了舍曲林作为新型小分子自噬诱导剂的潜力，并为通过靶向VDAC1治疗自噬相关疾病提供了新的候选药物。缩写：腺苷一磷酸（adenosine monophosphate，AMP）；腺苷酸活化蛋白激酶（AMP-activated protein kinase，AMPK）；三磷酸腺苷（adenosine triphosphate，ATP）；巴弗洛霉素A₁（bafilomycin A₁，Baf）；生物分子荧光互补（biomolecular fluorescence complementation，BiFC）；钙/钙调蛋白依赖性蛋白激酶激酶2（calcium/calmodulin dependent protein kinase kinase 2，CAMKK2/CAMKKB）；化合物C（compound C，CC）；药物亲和响应靶点稳定性（drug affinity responsive target stability，DARTS）；人脐静脉内皮细胞（human umbilical vein endothelial cells，HUVECs）；吲达品（indatraline，Inda）；丝氨酸/苏氨酸激酶11（serine/threonine kinase 11，STK11/LKB1）；微管相关蛋白tau（microtubule associated protein tau，MAPT）；微管相关蛋白1轻链3（microtubule associated protein 1 light chain 3，MAP1LC3/LC3）；3-甲基腺嘌呤（3-methyladenine，3-MA）；小鼠胚胎成纤维细胞（mouse embryonic fibroblasts，MEFs）；雷帕霉素靶蛋白激酶（mechanistic target of rapamycin kinase，MTOR）；磷脂酰肌醇3-激酶（phosphoinositide 3-kinase，PI3K）；雷帕霉素（rapamycin，Rapa）；舍曲林（sertraline，Sert）；核糖体蛋白S6激酶B1（ribosomal protein S6 kinase B1，RPS6KB1）；隔离体1（sequestosome 1，SQSTM1/p62）；溶质载体家族6成员4（solute carrier family 6 member 4，SLC6A4/SERT1）；转录因子EB（transcription factor EB，TFEB）；电压依赖性阴离子通道1（voltage dependent anion channel 1，VDAC1）；野生型（wild-type，WT）；渥曼青霉素（wortmannin，WM）。