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Controlling the Mitochondrial Protonmotive Force with Light to Impact Cellular Stress Resistance

Brandon J. Berry, Adam J. Trewin, Alexander S. Milliken, Aksana Baldzizhar, Andrea M. Amitrano, Minsoo Kim, Andrew P. Wojtovich
doi: https://doi.org/10.1101/742536
Brandon J. Berry
1University of Rochester Medical Center, Department of Pharmacology and Physiology, 575 Elmwood Ave., Rochester NY, 14642. Box 711/604. United States of America. Phone: 585-275-4613.
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Adam J. Trewin
2University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester NY, 14642 Box 711/604. United States of America. Phone: 585-275-4613.
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Alexander S. Milliken
1University of Rochester Medical Center, Department of Pharmacology and Physiology, 575 Elmwood Ave., Rochester NY, 14642. Box 711/604. United States of America. Phone: 585-275-4613.
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Aksana Baldzizhar
2University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester NY, 14642 Box 711/604. United States of America. Phone: 585-275-4613.
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Andrea M. Amitrano
3Department of Pathology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA
4Department of Microbiology and Immunology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA
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Minsoo Kim
3Department of Pathology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA
4Department of Microbiology and Immunology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA
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Andrew P. Wojtovich
1University of Rochester Medical Center, Department of Pharmacology and Physiology, 575 Elmwood Ave., Rochester NY, 14642. Box 711/604. United States of America. Phone: 585-275-4613.
2University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester NY, 14642 Box 711/604. United States of America. Phone: 585-275-4613.
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  • For correspondence: andrew_wojtovich@urmc.rochester.edu
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ABSTRACT

Mitochondrial respiration generates an electrochemical proton gradient across the mitochondrial inner membrane called the protonmotive force (PMF) to drive diverse functions and make ATP. Current techniques to manipulate the PMF are limited to its dissipation; there is no precise, reversible method to increase the PMF. To address this issue, we used an optogenetic approach and engineered a mitochondria-targeted light-activated proton pumping protein we called mitochondria-ON (mtON) to selectively increase the PMF. Here, mtON increased the PMF light dose-dependently, supported ATP synthesis, increased resistance to mitochondrial toxins, and modulated energy-sensing behavior in Caenorhabditis elegans. Moreover, transient mtON activation during hypoxia prevented the well-characterized adaptive response of hypoxic preconditioning. Our novel optogenetic approach demonstrated that a decreased PMF is both necessary and sufficient for hypoxia-stimulated stress resistance. Our results show that optogenetic manipulation of the PMF is a powerful tool to modulate metabolic and cell signaling outcomes.

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Posted August 21, 2019.
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Controlling the Mitochondrial Protonmotive Force with Light to Impact Cellular Stress Resistance
Brandon J. Berry, Adam J. Trewin, Alexander S. Milliken, Aksana Baldzizhar, Andrea M. Amitrano, Minsoo Kim, Andrew P. Wojtovich
bioRxiv 742536; doi: https://doi.org/10.1101/742536
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Controlling the Mitochondrial Protonmotive Force with Light to Impact Cellular Stress Resistance
Brandon J. Berry, Adam J. Trewin, Alexander S. Milliken, Aksana Baldzizhar, Andrea M. Amitrano, Minsoo Kim, Andrew P. Wojtovich
bioRxiv 742536; doi: https://doi.org/10.1101/742536

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