A Synthetic Ion Transporter That Disrupts Autophagy and Induces Apoptosis by Perturbing Cellular Chloride Concentrations

Overview

Journal Nat Chem

Specialty Chemistry

Date 2017 Jun 24

PMID 28644464

Citations 61

Authors

Nathalie Busschaert

Seong-Hyun Park

Kyung-Hwa Baek

Yoon Pyo Choi

Jinhong Park

Ethan N W Howe

Jennifer R Hiscock

Louise E Karagiannidis

Igor Marques

Vitor Felix

Wan Namkung

Jonathan L Sessler

Philip A Gale

Injae Shin

Affiliations

Soon will be listed here.

Abstract

Perturbations in cellular chloride concentrations can affect cellular pH and autophagy and lead to the onset of apoptosis. With this in mind, synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here, we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in lysosomal pH, which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.

Citing Articles

Uncovering the potent antimicrobial activity of squaramide based anionophores - chloride transport and membrane disruption.

Brennan L, Luo X, Mohammed F, Kavanagh K, Elmes R Chem Sci. 2025; 16(9):4075-4084.

PMID: 39906384 PMC: 11788822. DOI: 10.1039/d4sc01693a.

Off-On Photo- and Redox-Triggered Anion Transport Using an Indole-Based Hydrogen Bond Switch.

Ahmad M, Muir A, Langton M ACS Omega. 2024; 9(45):45572-45580.

PMID: 39554452 PMC: 11561614. DOI: 10.1021/acsomega.4c07880.

Tunable Cytosolic Chloride Indicators for Real-Time Chloride Imaging in Live Cells.

Morse J, Nadiveedhi M, Schmidt M, Tang F, Hladun C, Ganesh P bioRxiv. 2024; .

PMID: 39149292 PMC: 11326291. DOI: 10.1101/2024.08.08.606814.

Platinum-based metal complexes as chloride transporters that trigger apoptosis.

Wang P, Fares M, Eladwy R, Bhuyan D, Wu X, Lewis W Chem Sci. 2024; 15(29):11584-11593.

PMID: 39055016 PMC: 11268493. DOI: 10.1039/d4sc02115k.

Genome-wide identification and expression analysis of the HAK/KUP/KT gene family in Moso bamboo.

Guo H, Tan J, Jiao Y, Huang B, Ma R, Ramakrishnan M Front Plant Sci. 2024; 15:1331710.

PMID: 38595761 PMC: 11002169. DOI: 10.3389/fpls.2024.1331710.

References

Busschaert N, Elmes R, Czech D, Wu X, Kirby I, Peck E . Thiosquaramides: pH switchable anion transporters. Chem Sci. 2015; 5(9):3617-3626. PMC: 4486358. DOI: 10.1039/C4SC01629G. View

Tzung S, Kim K, Basanez G, Giedt C, Simon J, Zimmerberg J . Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol. 2001; 3(2):183-91. DOI: 10.1038/35055095. View

Creasy B, Hartmann C, White F, McCoy K . New assay using fluorogenic substrates and immunofluorescence staining to measure cysteine cathepsin activity in live cell subpopulations. Cytometry A. 2007; 71(2):114-23. DOI: 10.1002/cyto.a.20365. View

Yu S, Canzoniero L, Choi D . Ion homeostasis and apoptosis. Curr Opin Cell Biol. 2001; 13(4):405-11. DOI: 10.1016/s0955-0674(00)00228-3. View

Stauber T, Jentsch T . Chloride in vesicular trafficking and function. Annu Rev Physiol. 2012; 75:453-77. DOI: 10.1146/annurev-physiol-030212-183702. View

Newmeyer D, Ferguson-Miller S . Mitochondria: releasing power for life and unleashing the machineries of death. Cell. 2003; 112(4):481-90. DOI: 10.1016/s0092-8674(03)00116-8. View

Mizushima N, Komatsu M . Autophagy: renovation of cells and tissues. Cell. 2011; 147(4):728-41. DOI: 10.1016/j.cell.2011.10.026. View

Igney F, Krammer P . Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002; 2(4):277-88. DOI: 10.1038/nrc776. View

Yang Y, Hu L, Zheng H, Mao C, Hu W, Xiong K . Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol Sin. 2013; 34(5):625-35. PMC: 4002883. DOI: 10.1038/aps.2013.5. View

10.

Cho H, Gee H, Baek K, Ko S, Park J, Lee H . A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator. J Am Chem Soc. 2011; 133(50):20267-76. DOI: 10.1021/ja206762p. View

11.

Xie Z, Klionsky D . Autophagosome formation: core machinery and adaptations. Nat Cell Biol. 2007; 9(10):1102-9. DOI: 10.1038/ncb1007-1102. View

12.

Bortner C, Cidlowski J . Uncoupling cell shrinkage from apoptosis reveals that Na+ influx is required for volume loss during programmed cell death. J Biol Chem. 2003; 278(40):39176-84. DOI: 10.1074/jbc.M303516200. View

13.

Saha T, Hossain M, Saha D, Lahiri M, Talukdar P . Chloride-Mediated Apoptosis-Inducing Activity of Bis(sulfonamide) Anionophores. J Am Chem Soc. 2016; 138(24):7558-67. DOI: 10.1021/jacs.6b01723. View

14.

Hosogi S, Kusuzaki K, Inui T, Wang X, Marunaka Y . Cytosolic chloride ion is a key factor in lysosomal acidification and function of autophagy in human gastric cancer cell. J Cell Mol Med. 2014; 18(6):1124-33. PMC: 4508152. DOI: 10.1111/jcmm.12257. View

15.

Li Z, Deng L, Chen J, Zhou C, Chen W . Does lipophilicity affect the effectiveness of a transmembrane anion transporter? Insight from squaramido-functionalized bis(choloyl) conjugates. Org Biomol Chem. 2015; 13(48):11761-9. DOI: 10.1039/c5ob01920f. View

16.

Li P, Nijhawan D, Budihardjo I, Srinivasula S, Ahmad M, Alnemri E . Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91(4):479-89. DOI: 10.1016/s0092-8674(00)80434-1. View

17.

Tsukimoto M, Harada H, Ikari A, Takagi K . Involvement of chloride in apoptotic cell death induced by activation of ATP-sensitive P2X7 purinoceptor. J Biol Chem. 2004; 280(4):2653-8. DOI: 10.1074/jbc.M411072200. View

18.

Williams D, Ko S, Park S, Lee M, Shin I . An apoptosis-inducing small molecule that binds to heat shock protein 70. Angew Chem Int Ed Engl. 2008; 47(39):7466-9. DOI: 10.1002/anie.200802801. View

19.

Waterhouse N, Goldstein J, von Ahsen O, Schuler M, Newmeyer D, Green D . Cytochrome c maintains mitochondrial transmembrane potential and ATP generation after outer mitochondrial membrane permeabilization during the apoptotic process. J Cell Biol. 2001; 153(2):319-28. PMC: 2169468. DOI: 10.1083/jcb.153.2.319. View

20.

DiCiccio J, Steinberg B . Lysosomal pH and analysis of the counter ion pathways that support acidification. J Gen Physiol. 2011; 137(4):385-90. PMC: 3068279. DOI: 10.1085/jgp.201110596. View