TY - JOUR
T1 - Optogenetic control of mitochondrial metabolism & Ca2+ signaling by mitochondria-Targeted opsins
AU - Tkatch, Tatiana
AU - Greotti, Elisa
AU - Baranauskas, Gytis
AU - Pendin, Diana
AU - Roy, Soumitra
AU - Nita, Luliaoana I.
AU - Wettmarshausen, Jennifer
AU - Prigge, Matthias
AU - Yizhar, Ofer
AU - Shirihai, Orian S.
AU - Fishman, Daniel
AU - Hershfinkel, Michal
AU - Fleidervish, Ilya A.
AU - Perocchi, Fabiana
AU - Pozzan, Tullio
AU - Sekler, Israel
PY - 2017/6/27
Y1 - 2017/6/27
N2 - 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.
AB - 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.
KW - Ca signaling
KW - Mitochondria
KW - Mitochondrial membrane potential
KW - Optogenetic
UR - http://www.scopus.com/inward/record.url?scp=85021395235&partnerID=8YFLogxK
U2 - 10.1073/pnas.1703623114
DO - 10.1073/pnas.1703623114
M3 - Article
C2 - 28611221
AN - SCOPUS:85021395235
SN - 0027-8424
VL - 114
SP - E5167-E5176
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -