Optogenetic control of mitochondrial metabolism & Ca2+ signaling by mitochondria-Targeted opsins

Tatiana Tkatch, Elisa Greotti, Gytis Baranauskas, Diana Pendin, Soumitra Roy, Luliaoana I. Nita, Jennifer Wettmarshausen, Matthias Prigge, Ofer Yizhar, Orian S. Shirihai, Daniel Fishman, Michal Hershfinkel, Ilya A. Fleidervish, Fabiana Perocchi, Tullio Pozzan*, Israel Sekler

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Key mitochondrial functions such as ATP production, Ca2+ uptake and release, and substrate accumulation depend on the proton electrochemical gradient (ΔμH+) across the inner membrane. Although several drugs can modulate ΔμH+, their effects are hardly reversible, and lack cellular specificity and spatial resolution. Although channelrhodopsins are widely used to modulate the plasma membrane potential of excitable cells, mitochondria have thus far eluded optogenetic control. Here we describe a toolkit of optometabolic constructs based on selective targeting of channelrhodopsins with distinct functional properties to the inner mitochondrial membrane of intact cells. We show that our strategy enables a light-dependent control of the mitochondrial membrane potential (Δψm) and coupled mitochondrial functions such as ATP synthesis by oxidative phosphorylation, Ca2+ dynamics, and respiratory metabolism. By directly modulating Δψm, the mitochondriatargeted opsinswere used to control complex physiological processes such as spontaneous beats in cardiac myocytes and glucose-dependent ATP increase in pancreatic β-cells. Furthermore, our optometabolic tools allow modulation of mitochondrial functions in single cells and defined cell regions.

Original languageEnglish (US)
Pages (from-to)E5167-E5176
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number26
DOIs
StatePublished - Jun 27 2017

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Keywords

  • Ca signaling
  • Mitochondria
  • Mitochondrial membrane potential
  • Optogenetic

ASJC Scopus subject areas

  • General

Cite this

Tkatch, T., Greotti, E., Baranauskas, G., Pendin, D., Roy, S., Nita, L. I., Wettmarshausen, J., Prigge, M., Yizhar, O., Shirihai, O. S., Fishman, D., Hershfinkel, M., Fleidervish, I. A., Perocchi, F., Pozzan, T., & Sekler, I. (2017). Optogenetic control of mitochondrial metabolism & Ca2+ signaling by mitochondria-Targeted opsins. Proceedings of the National Academy of Sciences of the United States of America, 114(26), E5167-E5176. https://doi.org/10.1073/pnas.1703623114