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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Sidlauskaite, E; Gibson, JW; Megson, IL; Whitfield, PD; Tovmasyan, A; Batinic-Haberle, I; Murphy, MP; Moult, PR; Cobley, JN

Published Date

  • June 2018

Published In

Volume / Issue

  • 16 /

Start / End Page

  • 344 - 351

PubMed ID

  • 29587245

Pubmed Central ID

  • 29587245

Electronic International Standard Serial Number (EISSN)

  • 2213-2317

Digital Object Identifier (DOI)

  • 10.1016/j.redox.2018.03.012

Language

  • eng

Conference Location

  • Netherlands