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 journalArticle

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Avery, M. A., Rooney, T. M., Pandya, J. D., Wishart, T. M., Gillingwater, T. H., Geddes, J. W., Sullivan, P. G., & Freeman, M. R. (2012). Wld S prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca 2+ buffering. Current Biology, 22(7), 596-600. https://doi.org/10.1016/j.cub.2012.02.043