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

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.

Synapse Pruning: Mitochondrial ROS with Their Hands on the Shears

“…Consistent with experimental data in skeletal muscle wherein contractile activity (i.e., exercise) decreases whereas inactivity increases mitochondrial O 2 .− /H 2 O 2 production . In addition, silencing NMJ activity with neurotoxins or endogenous synapse pruning cues increases mitochondrial (O 2 .− /H 2 O 2 ) in vivo . The above‐mentioned theoretical and experimental evidence strongly suggests that: mitochondrial O 2 .− /H 2 O 2 are endogenous synaptic activity sentinels.…”

Inhibition of Mitochondrial ROS by MitoQ Alleviates White Matter Injury and Improves Outcomes after Intracerebral Haemorrhage in Mice

“…Second is the proposed intervention for selective subcellular localization. Mitochondria are ROSproducing and primary oxidative stress-damaging organelles [17,39]. Clinical trial reported that CoQ10-targeted mitochondrial ROS therapy to reduce major adverse cardiovascular events, hospitalization rates, and mortality.…”

“…ROS are mainly produced by the Fenton reaction induced by iron overload after ICH, which occurs primarily in the mitochondria [13][14][15]. And the selective mitochondrial ROS scavengers are reported superior to nonselective ROS scavengers in the treatment of many redox diseases involving mitochondrial dysfunction [16][17][18]. Therefore, it is urgent to explore the protective effect of selective mitochondrial ROS scavenger on secondary injury of ICH.…”

Immunological Techniques to Assess Protein Thiol Redox State: Opportunities, Challenges and Solutions

“…Until recently, reversible subunit alpha oxidation had only been assessed by redox proteomics usually in either isolated mitochondria or disease models [131]. Intrigued by a possible physiological redox regulatory role, we asked whether the alpha subunit is reversibly oxidized in oocytes and zygotes from the key developmental model Xenopus laevis (X. laevis) [132][133][134]. We hypothesized that the alpha subunit would be reversibly oxidized in oocytes to prevent wasteful ATP hydrolysis [135], but that fertilization induced ADP may provide an instructive cue to relieve reversible thiol oxidation to initiate embryonic mitochondrial ATP synthesis [136].…”