Optogenetic Control of Mitochondrial Protonmotive Force to Impact Cellular Stress Resistance

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2020 Feb 12

PMID 32043300

Citations 23

Authors

Brandon J Berry

Adam J Trewin

Alexander S Milliken

Aksana Baldzizhar

Andrea M Amitrano

Yunki Lim

Minsoo Kim

Andrew P Wojtovich

Affiliations

Soon will be listed here.

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.

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References

Brennan J, Southworth R, Medina R, Davidson S, Duchen M, Shattock M . Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation. Cardiovasc Res. 2006; 72(2):313-21. DOI: 10.1016/j.cardiores.2006.07.019. View

Apfeld J, OConnor G, McDonagh T, DiStefano P, Curtis R . The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 2004; 18(24):3004-9. PMC: 535911. DOI: 10.1101/gad.1255404. View

Garrido C, Galluzzi L, Brunet M, Puig P, Didelot C, Kroemer G . Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 2006; 13(9):1423-33. DOI: 10.1038/sj.cdd.4401950. View

Jeon S . Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016; 48(7):e245. PMC: 4973318. DOI: 10.1038/emm.2016.81. View

Shabalina I, Nedergaard J . Mitochondrial ('mild') uncoupling and ROS production: physiologically relevant or not?. Biochem Soc Trans. 2011; 39(5):1305-9. DOI: 10.1042/BST0391305. View

Balaban R, KANTOR H, Katz L, Briggs R . Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science. 1986; 232(4754):1121-3. DOI: 10.1126/science.3704638. View

Wojtovich A, DiStefano P, Sherman T, Brookes P, Nehrke K . Mitochondrial ATP-sensitive potassium channel activity and hypoxic preconditioning are independent of an inwardly rectifying potassium channel subunit in Caenorhabditis elegans. FEBS Lett. 2012; 586(4):428-34. PMC: 3288502. DOI: 10.1016/j.febslet.2012.01.021. View

Hinchy E, Gruszczyk A, Willows R, Navaratnam N, Hall A, Bates G . Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J Biol Chem. 2018; 293(44):17208-17217. PMC: 6222118. DOI: 10.1074/jbc.RA118.002579. View

Ozcan C, Palmeri M, Horvath T, Russell K, Russell 3rd R . Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning. Am J Physiol Heart Circ Physiol. 2013; 304(9):H1192-200. PMC: 3652089. DOI: 10.1152/ajpheart.00592.2012. View

10.

Trewin A, Bahr L, Almast A, Berry B, Wei A, Foster T . Mitochondrial Reactive Oxygen Species Generated at the Complex-II Matrix or Intermembrane Space Microdomain Have Distinct Effects on Redox Signaling and Stress Sensitivity in . Antioxid Redox Signal. 2019; 31(9):594-607. PMC: 6657295. DOI: 10.1089/ars.2018.7681. View

11.

Hayakawa T, Kato K, Hayakawa R, Hisamoto N, Matsumoto K, Takeda K . Regulation of anoxic death in Caenorhabditis elegans by mammalian apoptosis signal-regulating kinase (ASK) family proteins. Genetics. 2011; 187(3):785-92. PMC: 3063672. DOI: 10.1534/genetics.110.124883. View

12.

Schmeisser S, Priebe S, Groth M, Monajembashi S, Hemmerich P, Guthke R . Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension. Mol Metab. 2013; 2(2):92-102. PMC: 3817383. DOI: 10.1016/j.molmet.2013.02.002. View

13.

Chouchani E, Pell V, Gaude E, Aksentijevic D, Sundier S, Robb E . Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014; 515(7527):431-435. PMC: 4255242. DOI: 10.1038/nature13909. View

14.

Perry S, Norman J, Barbieri J, Brown E, Gelbard H . Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. Biotechniques. 2011; 50(2):98-115. PMC: 3115691. DOI: 10.2144/000113610. View

15.

Takahashi M, Takagi S . Optical silencing of body wall muscles induces pumping inhibition in Caenorhabditis elegans. PLoS Genet. 2017; 13(12):e1007134. PMC: 5760098. DOI: 10.1371/journal.pgen.1007134. View

16.

Tkatch T, Greotti E, Baranauskas G, Pendin D, Roy S, Nita L . Optogenetic control of mitochondrial metabolism and Ca signaling by mitochondria-targeted opsins. Proc Natl Acad Sci U S A. 2017; 114(26):E5167-E5176. PMC: 5495261. DOI: 10.1073/pnas.1703623114. View

17.

Dasgupta N, Patel A, Scott B, Crowder C . Hypoxic preconditioning requires the apoptosis protein CED-4 in C. elegans. Curr Biol. 2007; 17(22):1954-9. PMC: 2134922. DOI: 10.1016/j.cub.2007.10.017. View

18.

Tsalik E, Hobert O . Functional mapping of neurons that control locomotory behavior in Caenorhabditis elegans. J Neurobiol. 2003; 56(2):178-97. DOI: 10.1002/neu.10245. View

19.

Xu M, Wang Y, Ayub A, Ashraf M . Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring mitochondrial membrane potential. Am J Physiol Heart Circ Physiol. 2001; 281(3):H1295-303. DOI: 10.1152/ajpheart.2001.281.3.H1295. View

20.

Chalmers S, Caldwell S, Quin C, Prime T, James A, Cairns A . Selective uncoupling of individual mitochondria within a cell using a mitochondria-targeted photoactivated protonophore. J Am Chem Soc. 2012; 134(2):758-61. PMC: 3260739. DOI: 10.1021/ja2077922. View