Wld S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca 2+ buffering

Michelle A. Avery, Timothy M. Rooney, Jignesh D. Pandya, Thomas M. Wishart, Thomas H. Gillingwater, James W. Geddes, Patrick G. Sullivan, Marc R. Freeman

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

Wld S (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 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 Ca 2+ and termination of mitochondrial movement - Wld 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 Ca 2+ buffering capacity. We propose that the enhanced Ca 2+ buffering capacity of Wld S+ mitochondria leads to increased mitochondrial motility, suppression of axotomy-induced Ca 2+ elevation in axons, and thereby suppression of Wallerian degeneration.

Original languageEnglish
Pages (from-to)596-600
Number of pages5
JournalCurrent Biology
Volume22
Issue number7
DOIs
StatePublished - Apr 10 2012

Bibliographical note

Funding Information:
All animal procedures were carried out in accordance with National Institutes of Health (NIH) guidelines and the Institutional Animal Care and Use Committee regulations of the University of Kentucky and the University of Edinburgh. This work was supported by NIH grant NS062993 (J.W.G. and P.G.S.), the Wellcome Trust (T.H.G. and M.R.F.), and NIH grant NS059991 (to M.R.F.). M.R.F. is an Early Career Scientist with the Howard Hughes Medical Institute. T.M.R. was supported by a grant from the Department of Defense (BC093796). We thank Vimala Bondada and Dingyuan Lou for preliminary work on the mitochondrial Ca 2+ dynamics and all members of the laboratories for helpful discussions.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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