Wld^S Prevents Axon Degeneration through Increased Mitochondrial Flux and Enhanced Mitochondrial Ca²⁺ Buffering

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• 作者：Michelle  ; A. Avery¹ ; Timothy  ; M. Rooney¹ ; Jignesh  ; D. Pandya³ ; Thomas  ; M. Wishart² ; Thomas  ; H. Gillingwater² ; James  ; W. Geddes³ ; Patrick  ; G. Sullivan³ ; Marc  ; R. Freeman¹ ; ^{marc.freeman@umassmed.edu}
• 刊名：Current Biology
• 出版年：2012
• 出版时间：10 April, 2012
• 年：2012
• 卷：22
• 期：7
• 页码：596-600
• 全文大小：567 K

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Summary

Wld^S (slow Wallerian degeneration) is a remarkable protein that can suppress Wallerian degeneration of axons and synapses [], but how it exerts this effect remains unclear []. Here, using Drosophila and mouse models, we identify mitochondria as a key site of action for Wld^S neuroprotective function. Targeting the NAD⁺ biosynthetic enzyme Nmnat to mitochondria was sufficient to fully phenocopy Wld^S, and Wld^S 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¡ªWld^S potently suppressed both of these events. Surprisingly, Wld^S also promoted increased basal mitochondrial motility in axons before injury, and genetically suppressing mitochondrial motility in?vivo dramatically reduced the protective effect of Wld^S. Intriguingly, purified mitochondria from Wld^S mice exhibited enhanced Ca²⁺ buffering capacity. We propose that the enhanced Ca²⁺ buffering capacity of Wld^S+ mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca²⁺ elevation in axons, and thereby suppression of Wallerian degeneration.