Journal
NANO RESEARCH
Volume 12, Issue 5, Pages 1009-1015Publisher
TSINGHUA UNIV PRESS
DOI: 10.1007/s12274-019-2331-x
Keywords
drug screening; mitochondria; lysosome; mitophagy; structured illumination microscopy
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Funding
- National Basic Research Program of China [2015CB856300]
- National Institutes of Health [NIH R35GM128837]
- Natural Science Foundation of Shandong Province [ZR2017PH072, ZR2017BH051, ZR2015QL007]
- Key Research and Development Plan of Shandong Province [2018GSF121033]
- University of Illinois at Urbana-Champaign
- Indiana University Office of the Vice Provost for Research
- NIH [NIH1S10OD024988-01]
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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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