The light-sensitive dimerizer zapalog reveals distinct modes of immobilization for axonal mitochondria

Controlling cellular processes with light can help elucidate their underlying mechanisms. Here we present zapalog, a small-molecule dimerizer that undergoes photolysis when exposed to blue light. Zapalog dimerizes any two proteins tagged with the FKBP and DHFR domains until exposure to light causes...

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Published inNature cell biology Vol. 21; no. 6; pp. 768 - 777
Main Authors Gutnick, Amos, Banghart, Matthew R., West, Emma R., Schwarz, Thomas L.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.06.2019
Nature Publishing Group
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Summary:Controlling cellular processes with light can help elucidate their underlying mechanisms. Here we present zapalog, a small-molecule dimerizer that undergoes photolysis when exposed to blue light. Zapalog dimerizes any two proteins tagged with the FKBP and DHFR domains until exposure to light causes its photolysis. Dimerization can be repeatedly restored with uncleaved zapalog. We implement this method to investigate mitochondrial motility and positioning in cultured neurons. Using zapalog, we tether mitochondria to constitutively active kinesin motors, forcing them down the axon towards microtubule (+) ends until their instantaneous release via blue light, which results in full restoration of their endogenous motility. We find that one-third of stationary mitochondria cannot be pulled away from their position and that these firmly anchored mitochondria preferentially localize to VGLUT1-positive presynapses. Furthermore, inhibition of actin polymerization with latrunculin A reduces this firmly anchored pool. On release from exogenous motors, mitochondria are preferentially recaptured at presynapses. Gutnick et al. design a light-sensitive small molecule, zapalog, which reversibly dimerizes any two proteins. Tethering mitochondria to active kinesin motors uncovers distinct modes of mitochondrial motility in axons.
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ISSN:1465-7392
1476-4679
DOI:10.1038/s41556-019-0317-2