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Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5167-E5176. doi: 10.1073/pnas.1703623114. Epub 2017 Jun 13.

Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins.

Author information

1
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8499000, Israel.
2
Institute of Neuroscience (Padua Section), Italian National Research Council, Padua, 35121, Italy.
3
Department of Biomedical Sciences, University of Padua, Padua, 35121, Italy.
4
Genzentrum, Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
5
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
6
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
7
Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095.
8
Institute of Neuroscience (Padua Section), Italian National Research Council, Padua, 35121, Italy; tullio.pozzan@unipd.it sekler@bgu.ac.il.
9
Venetian Institute of Molecular Medicine, Padua, 35121, Italy.
10
Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8499000, Israel; tullio.pozzan@unipd.it sekler@bgu.ac.il.

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 mitochondria-targeted opsins were 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.

KEYWORDS:

Ca2+ signaling; mitochondria; mitochondrial membrane potential; optogenetic

PMID:
28611221
PMCID:
PMC5495261
DOI:
10.1073/pnas.1703623114
[Indexed for MEDLINE]
Free PMC Article

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