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Nanoscale monitoring of mitochondria and lysosome interactions for drug screening and discovery

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Abstract

Technology advances in genomics, proteomics, and metabolomics largely expanded the pool of potential therapeutic targets. Compared with the in vitro setting, cell-based screening assays have been playing a key role in the processes of drug discovery and development. Besides the commonly used strategies based on colorimetric and cell viability, we reason that methods that capture the dynamic cellular events will facilitate optimal hit identification with high sensitivity and specificity. Herein, we propose a live-cell screening strategy using structured illumination microscopy (SIM) combined with an automated cell colocalization analysis software, Cellprofiler™, to screen and discover drugs for mitochondria and lysosomes interaction at a nanoscale resolution in living cells. This strategy quantitatively benchmarks the mitochondria-lysosome interactions such as mitochondria and lysosomes contact (MLC) and mitophagy. The automatic quantitative analysis also resolves fine changes of the mitochondria-lysosome interaction in response to genetic and pharmacological interventions. Super-resolution live-cell imaging on the basis of quantitative analysis opens up new avenues for drug screening and development by targeting dynamic organelle interactions at the nanoscale resolution, which could facilitate optimal hit identification and potentially shorten the cycle of drug discovery.

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Acknowledgements

This research was supported by the National Basic Research Program of China (No. 2015CB856300), National Institutes of Health (NIH R35GM128837 to J.D.), Natural Science Foundation of Shandong Province (Nos. ZR2017PH072, ZR2017BH051, and ZR2015QL007), and Key Research and Development Plan of Shandong Province (No. 2018GSF121033). K. Z. was supported by the University of Illinois at Urbana-Champaign. The Light Microscopy Imaging Center (LMIC) is supported in part with funds from Indiana University Office of the Vice Provost for Research. The 3D-SIM microscope was provided by NIH grant NIH1S10OD024988-01.

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Shandong University, Jinan, 250101, China

    Qixin Chen, Xintian Shao, Fei Liu, Fengshan Wang & Peixue Ling

  2. Shandong Academy of Pharmaceutical Science, Key Laboratory of Biopharmaceuticals, Engineering Laboratory of Polysaccharide Drugs, National-Local Joint Engineering Laboratory of Polysaccharide Drugs, Jinan, 250101, China

    Qixin Chen, Xintian Shao, Fei Liu & Peixue Ling

  3. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA

    Qixin Chen, Xintian Shao, Zhiqi Tian, Yang Chen & Jiajie Diao

  4. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Payel Mondal & Kai Zhang

  5. State Key Laboratory of Coordination Chemistry, Coordination Chemistry Institute, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China

    Weijiang He & Zijian Guo

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  1. Qixin Chen
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  2. Xintian Shao
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  10. Kai Zhang
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Correspondence to Peixue Ling, Weijiang He, Kai Zhang or Jiajie Diao.

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Chen, Q., Shao, X., Tian, Z. et al. Nanoscale monitoring of mitochondria and lysosome interactions for drug screening and discovery. Nano Res. 12, 1009–1015 (2019). https://doi.org/10.1007/s12274-019-2331-x

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