Intracellular electrophysiology

SCS Lectureship Award 2025 : 
The chemical milieu within an organelle has been evolutionarily optimized to enable the biochemistry that occurs within. We study how organelle function impacts cell function by mapping ions within the organelle lumens using a chemical imaging technology based on DNA. DNA self-assembles into molecularly precise, synthetic assemblies, commonly referred to as DNA nanodevices. Our DNA nanodevices are ion responsive, fluorescent probes that can be targeted to specific organelles(1). These reporters can then quantitatively image ions in organelles of cells in culture, in live multicellular organisms (2) as well as in cells obtained from blood draws (3) or skin biopsies from human patients (4). I will focus on recent findings from our lab. For example, where we solved a thirty-year problem in molecular sensing by mapping calcium in acidic organelles and identified the first example of a human lysosomal Ca2+ import mechanism (5), discovered that organelles have electrical behavior (6), and more recently, the discovery of sub-organellar pH gradients.

====

References:

1.     Tinker, J., et. al. Quantitative chemical imaging of organelles. Acc. Chem. Res., 2024, 57, 1906-1917.
2.     Narayanaswamy, N. et. al. A pH-correctable, DNA-based fluorescent reporter for organellar Calcium. Nat. Methods, 2019, 16, 95-102.
3.     Cui, C. et al. A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours. Nat. Nanotechnol., 2021, 16, 1394-1402.
4.     Leung, K., et al. A DNA nanomachine chemically resolves lysosomes in live cells. Nat. Nanotechnol., 2019, 14, 176-183.
5.     Zajac M., et al. A mechanism of lysosomal calcium entry. Sci. Adv. 2024, 10, eadk2317.
6.     Saminathan A., et al. A DNA based voltmeter for organelles. Nat. Nanotechnol. 2021, 16. 96-103.