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WldS Prevents Axon Degeneration through Increased Mitochondrial Flux and Enhanced Mitochondrial Ca2+ Buffering

WldS (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses [1], but how it exerts this effect remains unclear [2]. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for WldS neuroprotective functio...

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Bibliographic Details
Published in:Current biology 2012-04, Vol.22 (7), p.596-600
Main Authors: Avery, Michelle A., Rooney, Timothy M., Pandya, Jignesh D., Wishart, Thomas M., Gillingwater, Thomas H., Geddes, James W., Sullivan, Patrick G., Freeman, Marc R.
Format: Article
Language:English
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Summary:WldS (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses [1], but how it exerts this effect remains unclear [2]. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for WldS neuroprotective function. Targeting the NAD+ biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy WldS, and WldS was specifically localized to mitochondria in synaptic preparations from mouse brain. Axotomy of live wild-type axons induced a dramatic spike in axoplasmic Ca2+ and termination of mitochondrial movement—WldS potently suppressed both of these events. Surprisingly, WldS also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in vivo dramatically reduced the protective effect of WldS. Intriguingly, purified mitochondria from WldS mice exhibited enhanced Ca2+ buffering capacity. We propose that the enhanced Ca2+ buffering capacity of WldS+ mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca2+ elevation in axons, and thereby suppression of Wallerian degeneration. ► Axotomy induces dramatic Ca2+ bursts and termination of mitochondrial motility in axons ► WldS suppresses axonal Ca2+ bursts and maintains mitochondrial motility after axotomy ► WldS enhances mitochondrial Ca2+ uptake, resistance to mPTP, and mitochondrial motility ► Enhanced mitochondrial motility is essential for WldS neuroprotective function
ISSN:0960-9822
1879-0445
DOI:10.1016/j.cub.2012.02.043