Abstract

Lysosomes are multifunctional, subcellular organelles with roles in plasma membrane repair, autophagy, pathogen degradation and nutrient sensing. Dysfunctional lysosomes underlie Alzheimer’s disease, Parkinson’s disease and rare lysosomal storage diseases, but their contributions to these pathophysiologies are unclear. Live imaging has revealed lysosome subpopulations with different physical characteristics including dynamics, morphology or cellular localization. Here, we chemically resolve lysosome subpopulations using a DNA-based combination reporter that quantitatively images pH and chloride simultaneously in the same lysosome while retaining single-lysosome information in live cells. We call this technology two-ion measurement or 2-IM. 2-IM of lysosomes in primary skin fibroblasts derived from healthy individuals shows two main lysosome populations, one of which is absent in primary cells derived from patients with Niemann–Pick disease. When patient cells are treated with relevant therapeutics, the second population re-emerges. Chemically resolving lysosomes by 2-IM could enable decoding the mechanistic underpinnings of lysosomal diseases, monitoring disease progression or evaluating therapeutic efficacy.

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The data that support the plots within this paper and the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the University of Chicago Women’s Board, Pilot and Feasibility award from an NIDDK center grant P30DK42086 to the University of Chicago Digestive Diseases Research Core Center, MRSEC grant no. DMR-1420709, Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust, C-084, ANL-UChicago collaborative grant and University of Chicago start-up funds to Y.K. Y.K. is a Brain Research Foundation Fellow.

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Author notes

  1. These authors contributed equally: KaHo Leung, Kasturi Chakraborty.

Affiliations

  1. Department of Chemistry, The University of Chicago, Chicago, IL, USA

    • KaHo Leung
    • , Kasturi Chakraborty
    • , Anand Saminathan
    •  & Yamuna Krishnan
  2. Grossman Institute of Neuroscience, Quantitative Biology and Human Behavior, The University of Chicago, Chicago, IL, USA

    • KaHo Leung
    • , Kasturi Chakraborty
    • , Anand Saminathan
    •  & Yamuna Krishnan

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Contributions

K.L., K.C., A.S. and Y.K. designed the project. K.L., K.C. and A.S. performed experiments. K.L., K.C., A.S. and Y.K. analysed the data. K.L., K.C., A.S. and Y.K. wrote the paper. All authors discussed the results and gave input on the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Yamuna Krishnan.

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https://doi.org/10.1038/s41565-018-0318-5