Abstract
Synapses are particularly susceptible to the effects of advancing age, and mitochondria have long been implicated as organelles contributing to this compartmental vulnerability. Despite this, the mitochondrial molecular cascades promoting age-dependent synaptic demise remain to be elucidated. Here, we sought to examine how the synaptic mitochondrial proteome (including strongly mitochondrial associated proteins) was dynamically and temporally regulated throughout ageing to determine whether alterations in the expression of individual candidates can influence synaptic stability/morphology. Proteomic profiling of wild-type mouse cortical synaptic and non-synaptic mitochondria across the lifespan revealed significant age-dependent heterogeneity between mitochondrial subpopulations, with aged organelles exhibiting unique protein expression profiles. Recapitulation of aged synaptic mitochondrial protein expression at the Drosophila neuromuscular junction has the propensity to perturb the synaptic architecture, demonstrating that temporal regulation of the mitochondrial proteome may directly modulate the stability of the synapse in vivo.
Highlights
Mitochondria are highly dynamic and heterogeneous organelles that have the propensity to directly modulate synaptic architecture
We suggest that selective alterations in the synaptic mitochondrial proteome may contribute to the documented structural and functional perturbations occurring at synaptic terminals during advancing age
Synaptophysin, synaptic vesicle glycoprotein 2A (SV2A) and synaptotagmin-7 indicated significant enrichment in synaptic mitochondrial samples versus corresponding non-synaptic mitochondrial fractions suggesting purification of mitochondria derived from the synaptic compartment (Figure 2D)
Summary
Mitochondria are highly dynamic and heterogeneous organelles that have the propensity to directly modulate synaptic architecture. The number of “donut” mitochondria directly correlated with the size of the presynaptic active zone and a number of synaptic vesicles, in addition to the severity of cognitive impairment, suggesting that divergent mitochondrial morphologies may modulate synaptic transmission, plasticity and stability during advancing age [20,21,23]. Retrograde trafficking of mitochondria away from the presynaptic terminal mediates reductions in synaptic strength, whereas the presence of the organelles in apposition to the active zone promotes sustained neurotransmitter release and plastic modifications within the synaptic terminal [24,25], these data indicate that synaptic mitochondria play a fundamental role in regulating a multitude of properties at the synapse [23] and dynamic temporal modifications of this discrete population of organelles may significantly impact upon the structure and function of the compartment, promoting alterations in cognitive capacity
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