Mitochondrial ROS cause motor deficits induced by synaptic inactivity

implications for synapse pruning

Eva Sidlauskaite, Jack W. Gibson, Ian L. Megson, Philip D. Whitfield, Artak Tovmasyan, Ines Batinic-Haberle, Michael P. Murphy, Peter R. Moult, James N. Cobley

Research output: Contribution to journalArticle

6 Citations (Scopus)
12 Downloads (Pure)

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) antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bugarotoxin), 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.
Original languageEnglish
Pages (from-to)344-351
Number of pages8
JournalRedox Biology
Volume16
Early online date20 Mar 2018
DOIs
Publication statusPublished - Jun 2018

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Synapses
Reactive Oxygen Species
Neuromuscular Junction
Neurotoxins
Cues
Connectome
Paraquat
Mitochondria
Neuronal Plasticity
Porphyrins
Xenopus laevis
Manganese
Larva
Muscle
Antioxidants
Muscles

Cite this

Sidlauskaite, E., Gibson, J. W., Megson, I. L., Whitfield, P. D., Tovmasyan, A., Batinic-Haberle, I., ... Cobley, J. N. (2018). Mitochondrial ROS cause motor deficits induced by synaptic inactivity: implications for synapse pruning. Redox Biology, 16, 344-351. https://doi.org/10.1016/j.redox.2018.03.012
Sidlauskaite, Eva ; Gibson, Jack W. ; Megson, Ian L. ; Whitfield, Philip D. ; Tovmasyan, Artak ; Batinic-Haberle, Ines ; Murphy, Michael P. ; Moult, Peter R. ; Cobley, James N. / Mitochondrial ROS cause motor deficits induced by synaptic inactivity : implications for synapse pruning. In: Redox Biology. 2018 ; Vol. 16. pp. 344-351.
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author = "Eva Sidlauskaite and Gibson, {Jack W.} and Megson, {Ian L.} and Whitfield, {Philip D.} and Artak Tovmasyan and Ines Batinic-Haberle and Murphy, {Michael P.} and Moult, {Peter R.} and Cobley, {James N.}",
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Sidlauskaite, E, Gibson, JW, Megson, IL, Whitfield, PD, Tovmasyan, A, Batinic-Haberle, I, Murphy, MP, Moult, PR & Cobley, JN 2018, 'Mitochondrial ROS cause motor deficits induced by synaptic inactivity: implications for synapse pruning', Redox Biology, vol. 16, pp. 344-351. https://doi.org/10.1016/j.redox.2018.03.012

Mitochondrial ROS cause motor deficits induced by synaptic inactivity : implications for synapse pruning. / Sidlauskaite, Eva; Gibson, Jack W.; Megson, Ian L.; Whitfield, Philip D.; Tovmasyan, Artak; Batinic-Haberle, Ines; Murphy, Michael P.; Moult, Peter R.; Cobley, James N.

In: Redox Biology, Vol. 16, 06.2018, p. 344-351.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mitochondrial ROS cause motor deficits induced by synaptic inactivity

T2 - implications for synapse pruning

AU - Sidlauskaite, Eva

AU - Gibson, Jack W.

AU - Megson, Ian L.

AU - Whitfield, Philip D.

AU - Tovmasyan, Artak

AU - Batinic-Haberle, Ines

AU - Murphy, Michael P.

AU - Moult, Peter R.

AU - Cobley, James N.

PY - 2018/6

Y1 - 2018/6

N2 - 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) antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bugarotoxin), 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.

AB - 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) antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bugarotoxin), 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.

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DO - 10.1016/j.redox.2018.03.012

M3 - Article

VL - 16

SP - 344

EP - 351

JO - Redox Biology

JF - Redox Biology

SN - 2213-2317

ER -