Mitochondrial ROS cause motor deficits induced by synaptic inactivity: implications for synapse pruning

Sidlauskaite, E., Gibson, J. W., Megson, I. L., Whitfield, P. D., Tovmasyan, A., Batinic-Haberle, I., Murphy, M. P., Moult, P. R. and Cobley, J. N. (2018) Mitochondrial ROS cause motor deficits induced by synaptic inactivity: implications for synapse pruning. Redox Biology, 16, pp. 344-351. (doi: 10.1016/j.redox.2018.03.012) (PMID:29587245) (PMCID:PMC5953219)

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Abstract

Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles. We resolved whether: (1) synaptic inactivity increases mitochondrial ROS; and (2) chemically heterogeneous antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bungarotoxin), nerve (α-latrotoxin) targeted neurotoxins or an endogenous pruning cue (SPARC), synaptic inactivity increased mitochondrial ROS in vivo. The manganese porphyrins MnTE-2-PyP5+ and/or MnTnBuOE-2-PyP5+ blocked mitochondrial ROS to significantly reduce neurotoxin and endogenous pruning cue induced motor deficits. Selectively inducing mitochondrial ROS—using mitochondria-targeted Paraquat (MitoPQ)—recapitulated synaptic inactivity induced motor deficits; which were significantly reduced by blocking mitochondrial ROS with MnTnBuOE-2-PyP5+. We unveil mitochondrial ROS as synaptic activity sentinels that regulate the phenotypical consequences of forced synaptic inactivity at the NMJ. Our novel results are relevant to pruning because synaptic inactivity is one of its defining features.

Item Type:Articles
Additional Information:J.N.C. & P.R.M. acknowledge the generous financial support of the Carnegie Trust (R70103) and Royal Society (RG150598). J.N.C. thanks Dr Ania Noble (Portsmouth University) for kindly providing X. laevis. JNC is supported by Highlands and Islands Enterprise funding (HIEJNC007).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Moult, Dr Peter
Authors: Sidlauskaite, E., Gibson, J. W., Megson, I. L., Whitfield, P. D., Tovmasyan, A., Batinic-Haberle, I., Murphy, M. P., Moult, P. R., and Cobley, J. N.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Redox Biology
Publisher:Elsevier
ISSN:2213-2317
Published Online:20 March 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Redox Biology 16: 344-351
Publisher Policy:Reproduced under a Creative Commons License

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