Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance. (11th February 2020)

• Record Type: Journal Article
• Authors: Berry, Brandon J; Trewin, Adam J; Milliken, Alexander S; Baldzizhar, Aksana; Amitrano, Andrea M; Lim, Yunki; Kim, Minsoo; Wojtovich, Andrew P
• Is Part Of: EMBO reports. Volume 21:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-11
• Subjects: anoxia -- hypoxia -- ischemia reperfusion -- metabolism -- uncoupling; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201949113
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Mitochondrial respiration generates an electrochemical proton gradient across the mitochondrial inner membrane called protonmotive force (PMF) to drive diverse functions and synthesize ATP. Current techniques to manipulate the PMF are limited to its dissipation; yet, there is no precise and reversible method to increase the PMF. To address this issue, we aimed to use an optogenetic approach and engineered a mitochondria‐targeted light‐activated proton pump that we name mitochondria‐ON (mtON) to selectively increase the PMF in Caenorhabditis elegans . Here we show that mtON photoactivation increases the PMF in a dose‐dependent manner, supports ATP synthesis, increases resistance to mitochondrial toxins, and modulates energy‐sensing behavior. Moreover, transient mtON activation during hypoxic preconditioning prevents the well‐characterized adaptive response of hypoxia resistance. Our results show that optogenetic manipulation of the PMF is a powerful tool to modulate metabolism and cell signaling. Synopsis: mtON is an optogenetic tool that allows elevation of mitochondrial PMF independent of mitochondrial respiration. By using this tool, this study reveals that a drop in PMF is required for hypoxic adaptation and AMPK mediated starvation response. Photoactivation of mtON increases mitochondrial protonmotive force in worms. mtON photoactivation rescues mitochondrial dysfunction that is induced both pharmacologically and genetically. mtON photoactivation prevents activation of AMPK signalling upon nutrient starvation. mtON photoactivation during hypoxic preconditioning blunts evolutionarily conserved hypoxia resistance. Abstract : mtON is an optogenetic tool that allows elevation of mitochondrial PMF independent of mitochondrial respiration. By using this tool, this study reveals that a drop in PMF is required for hypoxic adaptation and AMPK mediated starvation response.