MitoSNARE Assembly and Disassembly Factors Regulate Basal Autophagy and Aging in C. elegans

Abstract

SNARE proteins reside between opposing membranes and facilitate vesicle fusion, a physiological process ubiquitously required for secretion, endocytosis and autophagy. With age, neurosecretory SNARE activity drops and is pertinent to age-associated neurological disorders. Despite the importance of SNARE complex assembly and disassembly in membrane fusion, their diverse localization hinders the complete understanding of their function. Here, we revealed a subset of SNARE proteins, the syntaxin SYX-17, the synaptobrevins VAMP-7, SNB-6 and the tethering factor USO-1, to be either localized or in close proximity to mitochondria, in vivo. We term them mitoSNAREs and show that animals deficient in mitoSNAREs exhibit increased mitochondria mass and accumulation of autophagosomes. The SNARE disassembly factor NSF-1 seems to be required for the effects of mitoSNARE depletion. Moreover, we find mitoSNAREs to be indispensable for normal aging in both neuronal and non-neuronal tissues. Overall, we uncover a previously unrecognized subset of SNAREs that localize to mitochondria and propose a role of mitoSNARE assembly and disassembly factors in basal autophagy regulation and aging.

The role of the synaptic vesicle protein SV2A in regulating mitochondrial morphology and autophagy

“…In contrast, Stx4 enrichment at mitochondria favors mitochondrial fusion 36 . Regarding the effects on autophagy, SYN17 and C. elegans SNARE proteins such vamp-7 share similar effects on autophagy 53 . In contrast, we observed a significant decrease in autophagic flux upon SV2A KD in SH-SY5Y cells suggesting that SV2A improves autophagy/mitophagy.…”

“…Given the dynamic nature of mitochondria involving continuous membrane fission and fusion akin to synaptic vesicles, we hypothesize that SV2A may exert similar regulatory effects on mitochondrial dynamics. Recent findings indicated mitochondrial localization of a subset of SNARE proteins which are well recognized as regulators of 5 presynaptic neurotransmitter release and endocytotic recycling of synaptic vesicles 34 . Syntaxin17 (SYN17) knockdown leads to elongated mitochondria affecting DRP1 localization and activation 35 .…”

“…Other SNARE proteins known for their mitochondrial localization are e.g. SNAP23 as well VAMPB1 34 . They are also known to affect / modulate / influence autophagy.…”