Synapse Formation Activates a Transcriptional Program for Persistent Enhancement in the Bi-directional Transport of Mitochondria

Abstract

SUMMARY Mechanisms that regulate the bi-directional transport of mitochondria in neurons for maintaining functional synaptic connections are poorly understood. Here, we show that in the pre-synaptic sensory neurons of the Aplysia gill withdrawal reflex, the formation of functional synapses leads to persistent enhancement in the flux of bi-directional mitochondrial transport. In the absence of a functional synapse, activation of cAMP signaling is sufficient to enhance bi-directional transport in sensory neurons. Furthermore, persistent enhancement in transport does not depend on NMDA and AMPA receptor signaling nor signaling from the post-synaptic neuronal cell body, but it is dependent on transcription and protein synthesis in the pre-synaptic neuron. We identified ~4,000 differentially enriched transcripts in pre-synaptic neurons, suggesting a long-term change in the transcriptional program produced by synapse formation. These results provide insights into the regulation of bi-directional mitochondrial transport for synapse maintenance.

Axonal transport and neurological disease

“…[H2] Studying axonal transport in vivo. In vitro systems and ex vivo tissue preparations do not always accurately replicate the in vivo environment, especially when modelling dynamic, tightly regulated processes such as axonal transport [109][110][111][112] , which can be influenced by noncell-autonomous signalling 113,114 and cell-cell interactions 115,116 . This issue is particularly pertinent for discriminating between cell-autonomous and non-cell-autonomous pathomechanisms, which have been shown to contribute to diverse neuropathologies to varying degrees 117 .…”

Transient heat release during induced mitochondrial proton uncoupling

“…In comparison, the electrical heat at the onset of pmf dissipation from a single mitochondrion is ~20 pW () 13 , which may be dependent on the cell lines, and the proton pool. The density of mitochondria in axons 47 can be as high as 0.6 μm −2 . However, in the soma of Aplysia neurons, there can be a reticulum 48,49 of several functionally fused mitochondria as well as numerous individual mitochondria 50,51 .…”

Temporal Control of Axonal Transport: The Extreme Case of Organismal Ageing

“…Recognising viable targets to restore cargo transport during ageing may therefore prove essential. Motor abundance (Puthanveettil et al, 2008; Li et al, 2016; Vagnoni and Bullock, 2018; Badal et al, 2019) and the activity of signalling pathways linked to lifespan extension (Li et al, 2016; Morsci et al, 2016; Vagnoni and Bullock, 2018) are potential candidates, even though these studies are limited to only few cargoes. More work is needed to understand the general mechanisms governing intracellular trafficking during ageing in a bid to target axonal transport, in conjunction with other cellular processes (Riera and Dillin, 2015), to improve the health of neurons during ageing (Figure 1).…”

“…Despite their lack of motility relative to other cargoes, reduction in mitochondrial movements is linked to decreased cellular health during ageing and disease, and declining transport appears to be an evolutionary conserved hallmark of ageing across several neuronal subtypes, from invertebrates to mammals (Takihara et al, 2015; Morsci et al, 2016; Vagnoni et al, 2016). On the other hand, upregulation of mitochondrial transport, for instance by boosting the cAMP-PKA pathway, correlates with increased cellular health in aged Drosophila neurons (Vagnoni and Bullock, 2018) and underlies synapse formation in Aplysia neurons (Badal et al, 2019). In fruit flies and worms, upregulation of mitochondrial transport also correlates with the suppression of Wallerian degeneration (Avery et al, 2012) and is protective against axotomy-triggered degeneration (Rawson et al, 2014).…”